新型N-芳基胺基三氮唑核苷的合成、表征及生物活性测试
|
摘要
核苷类似物是一类重要的抗病毒和抗肿瘤药物，主要通过对天然核苷的核糖或者碱基部分进行修饰得到。利巴韦林(Ribavirin)作为最具代表性的核苷类似物，是第一个人工合成的以非天然的三氮唑为碱基的药物小分子，其广谱的抗病毒活性使其至今仍活跃在临床一线，目前仍是临床治疗丙型肝炎病毒(HCV)的重要药物小分子。
本实验室长期致力于发展新型的三氮唑核苷类似物，旨在寻找有抗病毒和抗肿瘤活性的药物小分子。三氮唑是非天然的碱基，不易被体内的各种酶识别，在体内的稳定性很好。而在三氮唑碱基中引入芳香基团，增大了碱基芳香体系，从而可以增强其与生物靶标的相互作用。同时，芳香基团的修饰可能会增强三氮唑核苷与核酸或其他生物靶标之间的结合能力。这就是我们实验室多年来一直不断发展三氮唑核苷化学的初衷。我们通过运用各种现代有机合成手段对三氮唑碱基进行修饰，合成了一系列结构新颖的芳基三氮唑核苷类似物，确实发现了不少有抗病毒和抗肿瘤活性的三氮唑小分子，并且获得了两个国际专利。
在本论文中，我们的工作重点是寻找高效的合成手段得到芳胺基三氮唑核苷类似物(图1)。这是因为在前期的工作中，我们发现一些芳胺基三氮唑核苷类似物(2-1，4-1)显示出了很好的生物活性，并且具有新的作用机理。然而，实验室前期工作用Chan-Lam反应来合成目标分子，此方法存在产率低、反应时间长、底物适应性差等缺点。因此在本论文中，我们对新的合成方法进行摸索和探讨，得到了几个切实有效地方法来制备目标产物。
图1三氮唑核苷目标产物
首先我们在实验室前期工作的基础上做了改进，即用微波促进的Chan-Lam反应来合成目标产物2-1(图2)。经过一系列条件优化后发现，新的合成策略虽然较前期工作大大缩短了反应时间，但是仍没有克服产率低、底物适应性差等缺点。
图2微波促进的Chan-Lam反应
接下来，我们把目光转向了Pd催化的Buchwald-Hartwig胺化反应上。我们发现两个三氮唑开环核苷异构体1和2，分别需要不同的配体，Synphos和Xantphos，来促进反应顺利进行(图3)。从底物扩展情况看，对于大多数芳基胺底物，都能得到满意的结果，相比Chan-Lam反应，这种配体调节的反应不仅提高了产率，缩短了反应时间，也大大拓展了芳基胺底物类型。但不同的三氮唑底物1和2需要不同的配体来促进反应，同时该催化体系不适用于目标分子3-1和4-1的合成。简言之，从三氮唑核苷角度讲，底物的范围还是有局限性。
图3Pd催化选择性合成N-芳基胺基三氮唑开环核苷
因此，我们进一步发展出了Pd/Synphos/Xantphos的混合配体体系，成功合成了各种芳胺基三氮唑核苷类似物和芳胺基嘌呤核苷类似物(图4)。这个新的混合配体体系非常高效，有着十分广泛的底物适应性，不但芳基胺底物没有限制，各种核苷类底物也都能顺利反应。更加值得一提的是，此混合配体体系还能活化碳-氯键，有效地促进氯代嘌呤核苷类似物的芳胺基化反应。结合核磁共振磷谱的研究结果，我们提出了混合配体体系中Pd催化的碳-氮成键反应机理，是基于两个独立的催化循环体系，而这两个催化循环体系是通过Pd络合物之间的平衡联系在一起的(图5)。目前，我们实验室正在利用混合配体体系，开发合成新的三氮唑核苷类似物。
图4混合配体体系中的碳-氮成键反应
图5推测的混合配体的机理
最后，我们对所有新合成的化合物都进行了抗HCV和抗肿瘤的生物活性测试。令人高兴的是，其中一部分化合物展现出良好的抑制抗药性胰腺癌细胞增殖的活性。这些成果进一步证明了我们最初的设计思路是合理的，为合成目标产物所做的各种化学合成上的努力是值得肯定的。目前，我们正在对这些活性化合物进行构效分析及其作用机理进行探索。
Nucleoside mimics, created by modification either on nucleobase and/or on theribose of the natural nucleosides, are a class of important candidates to search forantiviral and anticancer drugs. One of the best representatives is ribavirin, which bearsan unnatural but unique1,2,4-triazole heterocycle. Ribavirin is the first synthetictriazole nucleoside, which displays an extremely large spectrum of antiviral activity.Over a long period, ribavirin remained as the only clinically available small moleculeto treat the infection caused by hepatitis C.
We are interested in developing novel triazole nucleosides in the quest tosearching for antiviral and anticancer drug candidates. As we know, triazole is anunnatural base, the resulting triazole nucleosides may hence be resistant tonucleos(t)ide metabolizing enzymes and endowed with increased in vivo stability andefficiency. In addition, triazole heterocycle is a universal base for base-pairing, whichmay offer beneficial interaction with nucleic acids. Finally, expanding the triazolenucleobase by appending aromatic systems may favor stronger and more efficientbinding to biological targets. Based on these considerations, we have been activelyengaged in exploring various synthetic strategies during the last ten years to constructa molecular library consisting of structurally novel and diverse triazole nucleosidesmainly in the way of introducing π-conjugated systems onto the triazole nucleobase.
In this thesis, we are particularly concerned in developing highly efficientmethods to synthesize the N-arylaminotriazole nucleosides (Figure1). This is becauseour previous results showed that some of these nucleoside analogs (2-1,4-1)possessed of potent anticancer activity involving novel mechanisms of action.
Figure1The desired products
However, our previous synthesis based on Cu-mediated Chan-Lam reaction wasonly able to yield the N-aryl aminotriazole nucleosides (2-1,4-1), which was far fromsatisfaction as the synthesis suffered from long reaction time, large catalyst loading,low yields and narrow substrate scope of both aryl bronic acid and triazole nucleoside.We therefore explored several approaches for synthesizing this family of compounds during my PhD program.
We first attempted microwave irradiation to promote Chan-Lam C-N coupling.Whereas the reaction time was significantly reduced, no beneficial effect wasachieved with regards to improve the reaction yield, decrease the catalyst loading andenlarge the substrate scope etc (Figure2).
Figure2Microwave-assisted Chan-Lam reaction
We then turned our attention to Pd-catalyzed Buchwald-Hartwig amination anddiscovered highly reactive Pd/ligand systems employing the phosphor ligands,Synphos and Xantphos, for selective aryl amination with the5-and3-bromotriazoleacyclonucleoside isomers, respectively, affording the correspondingN-arylaminotriazole acyclonucleosides with good to excellent yields (Figure3). Theligand mediated C-N coupling provided us an exceptionally extended scope of arylamine but could not extend scope of triazole nucleoside, with the synthesis beinghandicapped with limited nucleoside starting materials.
Figure3Selective Buchwald-Hartwig Amination
We therefore developed a mixed-ligand system of Pd/Synphos/Xantphos, whichpromotes effectively C-N coupling in the synthesis of various N-arylaminotriazoleand N-arylaminopurine nucleoside analogues. This catalytic system is strikinglypowerful and efficient, allowing for unparalleled substrate scope and high productyields as well as promotion of C-Cl bond activation for C-N coupling. Further31PNMR studies led us to propose a general mechanism involving two independentcatalytic cycles between which Pd is shuttled (Figure5). Further development of mixed-ligand catalysts to promote synthesis of other types of triazole nucleosideanalogues is currently under the way in our group.
Figure4Mixed-ligand promoted aryl amination
Figure5Proposed mechanism of the mixed-ligand system
Finally, we assessed all of the newly synthesized N-aryl aminotriazolenucleosides for antiviral and anticancer test. Pleasingly, some of them displayedoutstanding anticancer activity against drug-resistant pancreatic cancer, with superiorpotency compared to gemcitabine, the current first-line drug to treat pancreatic cancer.This finding further confirmed and warranted the interest in and importance ofdeveloping efficient catalytic systems for synthesizing this special family ofnucleoside analogs. We are actively pursuing our efforts and endeavor in thisdirection.
本实验室长期致力于发展新型的三氮唑核苷类似物，旨在寻找有抗病毒和抗肿瘤活性的药物小分子。三氮唑是非天然的碱基，不易被体内的各种酶识别，在体内的稳定性很好。而在三氮唑碱基中引入芳香基团，增大了碱基芳香体系，从而可以增强其与生物靶标的相互作用。同时，芳香基团的修饰可能会增强三氮唑核苷与核酸或其他生物靶标之间的结合能力。这就是我们实验室多年来一直不断发展三氮唑核苷化学的初衷。我们通过运用各种现代有机合成手段对三氮唑碱基进行修饰，合成了一系列结构新颖的芳基三氮唑核苷类似物，确实发现了不少有抗病毒和抗肿瘤活性的三氮唑小分子，并且获得了两个国际专利。
在本论文中，我们的工作重点是寻找高效的合成手段得到芳胺基三氮唑核苷类似物(图1)。这是因为在前期的工作中，我们发现一些芳胺基三氮唑核苷类似物(2-1，4-1)显示出了很好的生物活性，并且具有新的作用机理。然而，实验室前期工作用Chan-Lam反应来合成目标分子，此方法存在产率低、反应时间长、底物适应性差等缺点。因此在本论文中，我们对新的合成方法进行摸索和探讨，得到了几个切实有效地方法来制备目标产物。
图1三氮唑核苷目标产物
首先我们在实验室前期工作的基础上做了改进，即用微波促进的Chan-Lam反应来合成目标产物2-1(图2)。经过一系列条件优化后发现，新的合成策略虽然较前期工作大大缩短了反应时间，但是仍没有克服产率低、底物适应性差等缺点。
图2微波促进的Chan-Lam反应
接下来，我们把目光转向了Pd催化的Buchwald-Hartwig胺化反应上。我们发现两个三氮唑开环核苷异构体1和2，分别需要不同的配体，Synphos和Xantphos，来促进反应顺利进行(图3)。从底物扩展情况看，对于大多数芳基胺底物，都能得到满意的结果，相比Chan-Lam反应，这种配体调节的反应不仅提高了产率，缩短了反应时间，也大大拓展了芳基胺底物类型。但不同的三氮唑底物1和2需要不同的配体来促进反应，同时该催化体系不适用于目标分子3-1和4-1的合成。简言之，从三氮唑核苷角度讲，底物的范围还是有局限性。
图3Pd催化选择性合成N-芳基胺基三氮唑开环核苷
因此，我们进一步发展出了Pd/Synphos/Xantphos的混合配体体系，成功合成了各种芳胺基三氮唑核苷类似物和芳胺基嘌呤核苷类似物(图4)。这个新的混合配体体系非常高效，有着十分广泛的底物适应性，不但芳基胺底物没有限制，各种核苷类底物也都能顺利反应。更加值得一提的是，此混合配体体系还能活化碳-氯键，有效地促进氯代嘌呤核苷类似物的芳胺基化反应。结合核磁共振磷谱的研究结果，我们提出了混合配体体系中Pd催化的碳-氮成键反应机理，是基于两个独立的催化循环体系，而这两个催化循环体系是通过Pd络合物之间的平衡联系在一起的(图5)。目前，我们实验室正在利用混合配体体系，开发合成新的三氮唑核苷类似物。
图4混合配体体系中的碳-氮成键反应
图5推测的混合配体的机理
最后，我们对所有新合成的化合物都进行了抗HCV和抗肿瘤的生物活性测试。令人高兴的是，其中一部分化合物展现出良好的抑制抗药性胰腺癌细胞增殖的活性。这些成果进一步证明了我们最初的设计思路是合理的，为合成目标产物所做的各种化学合成上的努力是值得肯定的。目前，我们正在对这些活性化合物进行构效分析及其作用机理进行探索。
Nucleoside mimics, created by modification either on nucleobase and/or on theribose of the natural nucleosides, are a class of important candidates to search forantiviral and anticancer drugs. One of the best representatives is ribavirin, which bearsan unnatural but unique1,2,4-triazole heterocycle. Ribavirin is the first synthetictriazole nucleoside, which displays an extremely large spectrum of antiviral activity.Over a long period, ribavirin remained as the only clinically available small moleculeto treat the infection caused by hepatitis C.
We are interested in developing novel triazole nucleosides in the quest tosearching for antiviral and anticancer drug candidates. As we know, triazole is anunnatural base, the resulting triazole nucleosides may hence be resistant tonucleos(t)ide metabolizing enzymes and endowed with increased in vivo stability andefficiency. In addition, triazole heterocycle is a universal base for base-pairing, whichmay offer beneficial interaction with nucleic acids. Finally, expanding the triazolenucleobase by appending aromatic systems may favor stronger and more efficientbinding to biological targets. Based on these considerations, we have been activelyengaged in exploring various synthetic strategies during the last ten years to constructa molecular library consisting of structurally novel and diverse triazole nucleosidesmainly in the way of introducing π-conjugated systems onto the triazole nucleobase.
In this thesis, we are particularly concerned in developing highly efficientmethods to synthesize the N-arylaminotriazole nucleosides (Figure1). This is becauseour previous results showed that some of these nucleoside analogs (2-1,4-1)possessed of potent anticancer activity involving novel mechanisms of action.
Figure1The desired products
However, our previous synthesis based on Cu-mediated Chan-Lam reaction wasonly able to yield the N-aryl aminotriazole nucleosides (2-1,4-1), which was far fromsatisfaction as the synthesis suffered from long reaction time, large catalyst loading,low yields and narrow substrate scope of both aryl bronic acid and triazole nucleoside.We therefore explored several approaches for synthesizing this family of compounds during my PhD program.
We first attempted microwave irradiation to promote Chan-Lam C-N coupling.Whereas the reaction time was significantly reduced, no beneficial effect wasachieved with regards to improve the reaction yield, decrease the catalyst loading andenlarge the substrate scope etc (Figure2).
Figure2Microwave-assisted Chan-Lam reaction
We then turned our attention to Pd-catalyzed Buchwald-Hartwig amination anddiscovered highly reactive Pd/ligand systems employing the phosphor ligands,Synphos and Xantphos, for selective aryl amination with the5-and3-bromotriazoleacyclonucleoside isomers, respectively, affording the correspondingN-arylaminotriazole acyclonucleosides with good to excellent yields (Figure3). Theligand mediated C-N coupling provided us an exceptionally extended scope of arylamine but could not extend scope of triazole nucleoside, with the synthesis beinghandicapped with limited nucleoside starting materials.
Figure3Selective Buchwald-Hartwig Amination
We therefore developed a mixed-ligand system of Pd/Synphos/Xantphos, whichpromotes effectively C-N coupling in the synthesis of various N-arylaminotriazoleand N-arylaminopurine nucleoside analogues. This catalytic system is strikinglypowerful and efficient, allowing for unparalleled substrate scope and high productyields as well as promotion of C-Cl bond activation for C-N coupling. Further31PNMR studies led us to propose a general mechanism involving two independentcatalytic cycles between which Pd is shuttled (Figure5). Further development of mixed-ligand catalysts to promote synthesis of other types of triazole nucleosideanalogues is currently under the way in our group.
Figure4Mixed-ligand promoted aryl amination
Figure5Proposed mechanism of the mixed-ligand system
Finally, we assessed all of the newly synthesized N-aryl aminotriazolenucleosides for antiviral and anticancer test. Pleasingly, some of them displayedoutstanding anticancer activity against drug-resistant pancreatic cancer, with superiorpotency compared to gemcitabine, the current first-line drug to treat pancreatic cancer.This finding further confirmed and warranted the interest in and importance ofdeveloping efficient catalytic systems for synthesizing this special family ofnucleoside analogs. We are actively pursuing our efforts and endeavor in thisdirection.
引文
[1] Sampath, D.; Rao, V. A.; Plunkett, W. Mechanisms of apoptosis induction by nucleoside analogs,Oncogene2003,22,9063-9074.
[2] Jordheim, L. P.; Dumontet, C. Review of recent studies on resistance to cytotoxicdeoxynucleoside analogues, Biochim. Biophys. Acta, Rev.2007,1776,138-159.
[3] Ewald, B.; Sampath, D.; Plunkett, W. Nucleoside analogs: Molecular mechanisms signaling celldeath, Oncogene2008,27,6522-6537.
[4] Herdewijn, P.; Editor Modified nucleosides in biochemistry, biotechnology and medicine;WILEY-VCH Verlag GmbH&Co. KGaA:Weinheim, Germany,2008.
[5] Galmarini, C. M.; Popowycz, F.; Joseph, B. Cytotoxic nucleoside analogues: Different strategiesto improve their clinical efficacy, Curr. Med. Chem.2008,15,1072-1082.
[6] Claire, S. Nucleoside mimetics: Their chemistry and biological properties, Advanced ChemistryTexts, Gordon and Beach Science Publishers, UK,2001.
[7] De Clercq, E. Antiviral drugs: Current state of the art, J. Clin. Virol.2001,22,73-89.
[8] De Clercq, E. Antiviral drugs in current clinical use, J. Clin. Virol.2004,30,115-133.
[9] De Clercq, E.; Holy, A. Acyclic nucleoside phosphonates: A key class of antiviral drugs, Nat RevDrug Discov2005,4,928-940.
[10] De Clercq, E. The design of drugs for hiv and hcv, Nat. Rev. Drug Discovery2007,6,1001-1018.
[11] Schaeffer, H. J.; Beauchamp, L.; De Miranda, P.; Elion, G. B.; Bauer, D. J.; Collins, P.9-(2-hydroxyethoxymethyl)guanine activity against viruses of the herpes group, Nature1978,272,583-585.
[12] Sidwell, R. W.; Huffman, J. H.; Khare, G. P.; Allen, L. B.; Witkowski, J. T.; Robins, R. K.Broad-spectrum antiviral activity of virazole.1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide,Science1972,177,705-706.
[13] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[14] Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Nucleoside analogues and nucleobases in cancertreatment, Lancet Oncol.2002,3,415-424.
[15] Witkowski, J. T.; Robins, R. K.; Sidwell, R. W.; Simon, L. N. Design, synthesis, and broadspectrum antiviral activity of1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides,J. Med. Chem.1972,15,1150-1154.
[16] Streeter, D. G.; Witkowski, J. T.; Khare, G. P.; Sidwell, R. W.; Bauer, R. J.; Robins, R. K.; Simon,L. N. Mechanism of action of1-β-d-ribofuranosyl-1'2,4-triazole-3-carboxamide (virazole), a newbroad-spectrum antiviral agent, Proc. Nat. Acad. Sci. U. S. A. FIELD Full Journal Title:Proceedings ofthe National Academy of Sciences of the United States of America1973,70,1174-1178.
[17] De Clercq, E. Strategies in the design of antiviral drugs, Nat. Rev. Drug Discovery2002,1,13-25.
[18] Assouline, S.; Culjkovic, B.; Cocolakis, E.; Rousseau, C.; Beslu, N.; Amri, A.; Caplan, S.; Leber,B.; Roy, D.-C.; Miller, W. H., Jr.; Borden, K. L. B. Molecular targeting of the oncogene eif4e in acutemyeloid leukemia (aml): A proof-of-principle clinical trial with ribavirin, Blood2009,114,257-260.
[19] Borden, K. L. B.; Culjkovic-Kraljacic, B. Ribavirin as an anti-cancer therapy: Acute myeloidleukemia and beyond?, Leuk. Lymphoma2010,51,1805-1815.
[20] Graci, J. D.; Cameron, C. E. Quasispecies, error catastrophe, and the antiviral activity ofribavirin, Virology2002,298,175-180.
[21] Crotty, S.; Maag, D.; Arnold, J. J.; Zhong, W.; Lau, J. Y. N.; Hong, Z.; Andino, R.; Cameron, C.E. The broad-spectrum antiviral ribonucleoside ribavirin is an rna virus mutagen, Nat. Med.2000,6,1375-1379.
[22] Crotty, S.; Cameron, C. E.; Andino, R. Rna virus error catastrophe: Direct molecular test byusing ribavirin, Proc. Natl. Acad. Sci. U. S. A.2001,98,6895-6900.
[23] Davis, G. L.; Esteban-Mur, R.; Rustgi, V.; Hoefs, J.; Gordon, S. C.; Trepo, C.; Shiffman, M. L.;Zeuzem, S.; Craxi, A.; Ling, M.-H.; Albrecht, J. Interferon alfa-2b alone or in combination withribavirin for the treatment of relapse of chronic hepatitis c, N. Engl. J. Med.1998,339,1493-1499.
[24] Berlin, J.; Benson, A. B., III Gemcitabine remains the standard of care for pancreatic cancer, Nat.Rev. Clin. Oncol.2010,7,135-137.
[25] Pierantoni, C.; Pagliacci, A.; Scartozzi, M.; Berardi, R.; Bianconi, M.; Cascinu, S. Pancreaticcancer: Progress in cancer therapy, Crit Rev Oncol Hematol2008,67,27-38.
[26] Huang, P.; Plunkett, W. Induction of apoptosis by gemcitabine, Semin. Oncol.1995,22,19-25.
[27] Rivera, F.; Lopez-Tarruella, S.; Vega-Villegas, M. E.; Salcedo, M. Treatment of advancedpancreatic cancer: From gemcitabine single agent to combinations and targeted therapy, Cancer Treat.Rev.2009,35,335-339.
[28] Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J. L. Pancreatic cancer, Lancet2004,363,1049-1057.
[29] http://www.pharmgkb.org/images/pathway/gemcitabine.png
[30] Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chemical synthesis of heterocyclic-sugarnucleoside analogues, Chem. Rev.2010,110,3337-3370.
[31] Claire, S. Nucleoside mimetics: Their chemistry and biologicalproperties, Advanced Chemistry Texts, Gordon and Beach Science Publishers, UK,2001.
[32] Minakawa, N.; Takeda, T.; Sasaki, T.; Matsuda, A.; Ueda, T. Nucleosides and nucleotides.96.Synthesis and antitumor activity of5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (eicar) andits derivatives, J. Med. Chem.1991,34,778-786.
[33] Yin, M.-b.; Rustum, Y. M. Comparative DNA strand breakage induced by fura and fdurd inhuman ileocecal adenocarcinoma (hct-8) cells: Relevance to cell growth inhibition, Cancer Commun.1991,3,45-51.
[34] Robins, M. J.; Barr, P. J. Nucleic acid related compounds.39. Efficient conversion of5-iodo to5-alkynyl and derived5-substituted uracil bases and nucleosides, J. Org. Chem.1983,48,1854-1862.
[35] Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.;Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler,R. R. Discovery of1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-n-[2-fluoro-4-
[(2'-dimethylaminomethyl) imidazol-1-yl]phenyl]-1h-pyrazole-5-carboxyamide hydrochloride(razaxaban), a highly potent, selective, and orally bioavailable factor xa inhibitor, J. Med. Chem.2005,48,1729-1744.
[36] Comprehensive Heterocyclic Chemistry II; Katritzky, A.R., Rees, C.W.,Eds.; Elsevier: Oxford,1996;
[37] http://www.drugs.com/top200.html
[38] http://www.drugs.com/top200.html
[39] Evano, G.; Blanchard, N.; Toumi, M. Copper-mediated coupling reactions and their applicationsin natural products and designed biomolecules synthesis, Chem. Rev.2008,108,3054-3131.
[40] Fischer, C.; Koenig, B. Palladium-and copper-mediated N-aryl bond formation reactions for thesynthesis of biological active compounds, Beilstein J. Org. Chem.2011,7,59-74, No10.
[41] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination,Angew. Chem., Int. Ed.2008,47,6338-6361.
[42] Rosemeyer, H. The chemodiversity of purine as a constituent of natural products, ChemBiodivers2004,1,361-401.
[43] Legraverend, M. Recent advances in the synthesis of purine derivatives and their precursors,Tetrahedron2008,64,8585-8603.
[44] Jacobson, K. A.; Van Galen, P. J. M.; Williams, M. Adenosine receptors: Pharmacology,structure-activity relationships, and therapeutic potential, J. Med. Chem.1992,35,407-422.
[45] Miller, C. O. Kinetin and related compounds in plant growth, Annu. Rev. Plant Physiol.1961,12,395-408.
[46] Brathe, A.; Gundersen, L.-L.; Rise, F.; Eriksen, A. B.; Vollsnes, A. V.; Wang, L. Synthesis of6-alkenyl-and6-alkynylpurines with cytokinin activity, Tetrahedron1999,55,211-228.
[47] Montgomery, J. A.; Hewson, K. Analogs of6-methyl-9β-d-ribofuranosylpurine, J. Med. Chem.1968,11,48-52.
[48] Wright, G. E.; Dudycz, L. W. Synthesis and characterization of N2-(p-n-butylphenyl)-2'-deoxyguanosine and its5'-triphosphate and their inhibition of hela DNA polymerase, J. Med.Chem.1984,27,175-181.
[49] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective N-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[50] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[51] Ullmann, F.; Bielecki, J. Synthesis in the biphenyl series. I, Ber. Dtsch. Chem. Ges.1901,34,2174-2185.
[52] Ullmann, F. A new path for preparing diphenylamine derivatives, Ber. Dtsch. Chem. Ges.1903,36,2382-2384.
[53] Goldberg, I. Phenylation in the presence of copper as catalyst, Ber. Dtsch. Chem. Ges.1906,39,1691-1692.
[54] Monnier, F.; Taillefer, M. Catalytic C-C, C-N, and C-O ullmann-type coupling reactions: Coppermakes a difference, Angew. Chem., Int. Ed.2008,47,3096-3099.
[55] Ullmann, F.; Sponagel, P. Phenylation of phenols, Ber. Dtsch. Chem. Ges.1905,38,2211-2212.
[56] Ley, S. V.; Thomas, A. W. Modern synthetic methods for copper-mediated C(aryl)-O, C(aryl)-N,and C(aryl)-S bond formation, Angew. Chem., Int. Ed.2003,42,5400-5449.
[57] Kunz, K.; Scholz, U.; Ganzer, D. Renaissance of ullmann and goldberg reactions-progress incopper catalyzed C-N-, C-O and C-S coupling, Synlett2003,2428-2439.
[58] Monnier, F.; Taillefer, M. Catalytic C-C, C-N, and C-O ullmann-type coupling reactions, Angew.Chem., Int. Ed.2009,48,6954-6971.
[59] Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. Accelerating effect induced by the structure of-amino acid in the copper-catalyzed coupling reaction of aryl halides with-amino acids. Synthesis ofbenzolactam-v8, J. Am. Chem. Soc.1998,120,12459-12467.
[60] Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. An efficient copper-catalyzed coupling of arylhalides with imidazoles, Tetrahedron Lett.1999,40,2657-2660.
[61] Goodbrand, H. B.; Hu, N.-X. Ligand-accelerated catalysis of the ullmann condensation:Application to hole conducting triarylamines, J. Org. Chem.1999,64,670-674.
[62] Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. Using intelligent/random libraryscreening to design focused libraries for the optimization of homogeneous catalysts: Ullmann etherformation, J. Am. Chem. Soc.2000,122,5043-5051.
[63] Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Highly efficient and mildcopper-catalyzed N-and C-arylations with aryl bromides and iodides, Chem.--Eur. J.2004,10,5607-5622.
[64] Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Mild conditions for copper-catalyzedN-arylation of pyrazoles, Eur. J. Org. Chem.2004,695-709.
[65] Ma, D.; Cai, Q. L-proline-promoted ullmann-type coupling reactions of aryl iodides with indoles,pyrroles, imidazoles or pyrazoles, Synlett2004,128-130.
[66] Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Preparation of N-aryl compounds by aminoacid-promoted ullmann-type coupling reactions, Synthesis2005,496-499.
[67] Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted Cu-catalyzed C-N bond formation betweenaryl halides and amines or N-containing heterocycles, J. Org. Chem.2005,70,5164-5173.
[68] Antilla, J. C.; Klapars, A.; Buchwald, S. L. The copper-catalyzed N-arylation of indoles, J. Am.Chem. Soc.2002,124,11684-11688.
[69] Altman, R. A.; Buchwald, S. L.4,7-dimethoxy-1,10-phenanthroline: An excellent ligand for theCu-catalyzed N-arylation of imidazoles, Org. Lett.2006,8,2779-2782.
[70] Altman, R. A.; Koval, E. D.; Buchwald, S. L. Copper-catalyzed N-arylation of imidazoles andbenzimidazoles, J. Org. Chem.2007,72,6190-6199.
[71] Zhu, R.; Xing, L.; Wang, X.; Cheng, C.; Su, D.; Hu, Y. Highly practical "Ligand-free-like"Copper-catalyzed N-arylation of azoles in lower nitrile solvents, Adv. Synth. Catal.2008,350,1253-1257.
[72] Tao, C. Z.; Li, J.; Cui, X.; Fu, Y.; Guo, Q. X. Cu-catalyzed cross-couplings under ligandlessconditions, Chin. Chem. Lett.2007,18,1199-1202.
[73] Li, J. J. In Name Reactions: A Collection of Detailed Reaction Mechanisms and SyntheticApplications,4th ed.; Springer: New York,2009,102.
[74] Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation,Tetrahedron Lett.1998,39,2941-2944.
[75] Lam, P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M. J.; Galemmo, R. A.; Fevig, J. M.;Teleha, C. A.; Alexander, R. S.; Smallwood, A. M.; Rossi, K. A.; Wright, M. R.; Bai, S. A.; He, K.;Luettgen, J. M.; Wong, P. C.; Knabb, R. M.; Wexler, R. R. Structure-based design of novelguanidine/benzamidine mimics: Potent and orally bioavailable factor Xa inhibitors as novelanticoagulants, J. Med. Chem.2003,46,4405-4418.
[76] Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Copper promotedC-N and C-O bond cross-coupling with phenyl and pyridylboronates, Tetrahedron Lett.2003,44,3863-3865.
[77] Singh, B. K.; Appukkuttan, P.; Claerhout, S.; Parmar, V. S.; Van der Eycken, E.Copper(ii)-mediated cross-coupling of arylboronic acids and2(1H)-pyrazinones facilitated bymicrowave irradiation with simultaneous cooling, Org. Lett.2006,8,1863-1866.
[78] Bekolo, H. Copper-mediated N-arylation of electron-deficient pyrroles and indoles, Can. J.Chem.2007,85,42-46.
[79] Wang, W.; Devasthale, P.; Farrelly, D.; Gu, L.; Harrity, T.; Cap, M.; Chu, C.; Kunselman, L.;Morgan, N.; Ponticiello, R.; Zebo, R.; Zhang, L.; Locke, K.; Lippy, J.; O'Malley, K.; Hosagrahara, V.;Zhang, L.; Kadiyala, P.; Chang, C.; Muckelbauer, J.; Doweyko, A. M.; Zahler, R.; Ryono, D.;Hariharan, N.; Cheng, P. T. W. Discovery of azetidinone acids as conformationally-constrained dualppar/γ agonists, Bioorg. Med. Chem. Lett.2008,18,1939-1944.
[80] Sreeramamurthy, K.; Ashok, E.; Mahendar, V.; Santoshkumar, G.; Das, P. Direct synthesis ofn-aryl derivatives of quinazolin-4(3h)-ones employing arylboronic acids in the presence of Cu(OAc)2,Synlett2011,721-724.
[81] Harmse, L.; van Zyl, R.; Gray, N.; Schultz, P.; Leclerc, S.; Meijer, L.; Doerig, C.; Havlik, I.Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitrogrowth of plasmodium falciparum, Biochem. Pharmacol.2001,62,341-348.
[82] Meijer, L.; Raymond, E. Roscovitine and other purines as kinase inhibitors. From starfishoocytes to clinical trials, Acc. Chem. Res.2003,36,417-425.
[83] Strouse, J. J.; Jegelnik, M.; Arterburn, J. B. Applications of boronic acids in selective C-C andC-N arylation of purines, Acta Chim. Slov.2005,52,187-199.
[84] Khalafi-Nezhad, A.; Zare, A.; Parhami, A.; Rad, M. N. S.; Nejabat, G. R. Regioselectiven-arylation of some pyrimidine and purine nucleobases, Synth. Commun.2006,36,3549-3562.
[85] Strouse, J. J.; Jeselnik, M.; Tapaha, F.; Jonsson, C. B.; Parker, W. B.; Arterburn, J. B. Coppercatalyzed arylation with boronic acids for the synthesis of N1-aryl purine nucleosides, Tetrahedron Lett.2005,46,5699-5702.
[86] Bakkestuen, A. K.; Gundersen, L.-L. Regioselective N-9arylation of purines employingarylboronic acids in the presence of Cu(ii), Tetrahedron Lett.2003,44,3359-3362.
[87] Yue, Y.; Zheng, Z.-G.; Wu, B.; Xia, C.-Q.; Yu, X.-Q. Copper-catalyzed cross-coupling reactionsof nucleobases with arylboronic acids: An efficient access to n-aryl nucleobases, Eur. J. Org. Chem.2005,5154-5157.
[88] Guram, A. S.; Rennels, R. A.; Buchwald, S. L. A simple catalytic method for the conversion ofaryl bromides to arylamines, Angew. Chem., Int. Ed.1995,34,1348-1350.
[89] Louie, J.; Hartwig, J. F. Palladium-catalyzed synthesis of arylamines from aryl halides.Mechanistic studies lead to coupling in the absence of tin reagents, Tetrahedron Lett.1995,36,3609-3612.
[90] Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. Insights into the origin of high activity andstability of catalysts derived from bulky, electron-rich monophosphinobiaryl ligands in thepd-catalyzed c-n bond formation, J. Am. Chem. Soc.2003,125,13978-13980.
[91] Muci, A. R.; Buchwald, S. L. Practical palladium catalysts for C-N and C-O bond formation,Top. Curr. Chem.2002,219,131-209.
[92] Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherificationof aryl halides, Acc. Chem. Res.2008,41,1534-1544.
[93] Kosugi, M.; Kameyama, M.; Migita, T. Palladium-catalyzed aromatic amination of arylbromides with N,N-diethylaminotributyltin, Chem. Lett.1983,927-928.
[94] Guram, A. S.; Buchwald, S. L. Palladium-catalyzed aromatic aminations with in situ generatedaminostannanes, J. Am. Chem. Soc.1994,116,7901-7902.
[95] Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. An improved catalyst system for aromaticcarbon-nitrogen bond formation: The possible involvement of bis(phosphine) palladium complexes askey intermediates, J. Am. Chem. Soc.1996,118,7215-7216.
[96] Driver, M. S.; Hartwig, J. F. A second-generation catalyst for aryl halide amination: Mixedsecondary amines from aryl halides and primary amines catalyzed by (dppf)PdCl2, J. Am. Chem. Soc.1996,118,7217-7218.
[97] Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Bite angle effects of diphosphines in C-Cand C-X bond forming cross coupling reactions, Chem. Soc. Rev.2009,38,1099-1118.
[98] Strieter, E. R.; Buchwald, S. L. Evidence for the formation and structure of palladacycles duringPd-catalyzed C-N bond formation with catalysts derived from bulky monophosphinobiaryl ligands,Angew. Chem. Int. Ed.2006,45,925-928.
[99] Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. On the nature of the active species in palladiumcatalyzed mizoroki-heck and suzuki-miyaura couplings-homogeneous or heterogeneous catalysis, acritical review, Adv. Synth. Catal.2006,348,609-679.
[100] Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Structural insights into active catalyst structuresand oxidative addition to (biaryl)phosphine-palladium complexes via density functional theory andexperimental studies, Organometallics2007,26,2183-2192.
[101] Barder, T. E.; Buchwald, S. L. Insights into amine binding to biaryl phosphine palladiumoxidative addition complexes and reductive elimination from biaryl phosphine arylpalladium amidocomplexes via density functional theory, J. Am. Chem. Soc.2007,129,12003-12010.
[102] M. Beller, A. Zapf, Palladium-Catalyzed Coupling Reactions for Industrial Fine ChemicalsSyntheses, in: Handbook of Organopalladium Chemistry for Organic Synthesis, Vol.1,(Ed.: E.-i.Negishi), Wiley, New York,2002, p.1209
[103] Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.; Dingerdissen, U.;Beller, M. New ligands for a general palladium-catalyzed amination of aryl and heteroaryl chlorides,Chem.--Eur. J.2004,10,2983-2990.
[104] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenuesfor modifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[105] Wagaw, S.; Buchwald, S. L. The synthesis of aminopyridines: A method employingpalladium-catalyzed carbon-nitrogen bond formation, J. Org. Chem.1996,61,7240-7241.
[106] Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. Palladium-catalyzed C-N bondformation: Facile and general synthesis of n6-aryl2'-deoxyadenosine analogues, J. Am. Chem. Soc.1999,121,6090-6091.
[107] De Riccardis, F.; Bonala, R. R.; Johnson, F. A general method for the synthesis of the N2-andN6-carcinogenic amine adducts of2'-deoxyguanosine and2'-deoxyadenosine, J. Am. Chem. Soc.1999,121,10453-10460.
[108] Riccardis, F. D.; Johnson, F. Chemical synthesis of cross-linked purine nucleosides, Org. Lett.2000,2,293-295.
[109] Pratap, R.; Parrish, D.; Gunda, P.; Venkataraman, D.; Lakshman, M. K. Influence of biarylphosphine structure on C-N and C-C bond formation, J. Am. Chem. Soc.2009,131,12240-12249.
[110] Thomson, P. F.; Lagisetty, P.; Balzarini, J.; De Clercq, E.; Lakshman, M. K.Palladium-catalyzed aryl amination reactions of6-bromo-and6-chloropurine nucleosides, Adv. Synth.Catal.2010,352,1728-1735.
[111] Champeil, E.; Pradhan, P.; Lakshman, M. K. Palladium-catalyzed synthesis of nucleosideadducts from bay-and fjord-region diol epoxides, J. Org. Chem.2007,72,5035-5045.
[112] Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. A new principle in combinatorial asymmetrictransition-metal catalysis: Mixtures of chiral monodentate p ligands, Angew. Chem. Int. Ed.2003,42,790-793.
[113] Reetz, M. T. Combinatorial transition-metal catalysis: Mixing monodentate ligands to controlenantio-, diastero-, and regioselectivity, Angew. Chem. Int. Ed.2008,47,2556-2588.
[114] Reetz, M. T.; Li, X. Mixtures of configurationally stable and fluxional atropisomericmonodentate p ligands in asymmetric rh-catalyzed olefin hydrogenation, Angew. Chem. Int. Ed.2005,44,2959-2962.
[115] Reetz, M. T.; Mehler, G. Mixtures of chiral and achiral monodentate ligands in asymmetricrh-catalyzed olefin hydrogenation: Reversal of enantioselectivity, Tetrahedron Lett.2003,44,4593-4596.
[116] Pena, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L.Improving conversion and enantioselectivity in hydrogenation by combining different monodentatephosphoramidites; a new combinatorial approach in asymmetric catalysis, Org. Biomol. Chem.2003,1,1087-1089.
[117] Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Simple mixedtricyclohexylphosphane-triarylphosphite complexes as extremely high-activity catalysts for the suzukicoupling of aryl chlorides, Angew. Chem. Int. Ed.2002,41,4120-4122.
[118] Fors, B. P.; Buchwald, S. L. A multiligand based Pd catalyst for C-N cross-coupling reactions, J.Am. Chem. Soc.2010,132,15914-15917.
[119] Tang, W.; Keshipeddy, S.; Zhang, Y.; Wei, X.; Savoie, J.; Patel, N. D.; Yee, N. K.; Senanayake,C. H. Efficient monophosphorus ligands for palladium-catalyzed miyaura borylation, Org. Lett.2011,13,1366-1369.
[120] Saito, S.; Oh-tani, S.; Miyaura, N. Synthesis of biaryls via a nickel(0)-catalyzed cross-couplingreaction of chloroarenes with arylboronic acids, J. Org. Chem.1997,62,8024-8030.
[121] Galland, J.-C.; Savignae, M.; Genet, J.-P. Cross-coupling of chloroarenes with boronic acidsusing a water-soluble nickel catalyst, Tetrahedron Lett.1999,40,2323-2326.
[122] Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. NiCl2(dppe)-catalyzed cross-coupling ofaryl mesylates, arenesulfonates, and halides with arylboronic acids, J. Org. Chem.2004,69,3447-3452.
[123] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Corcoran, P.; Rosen, B. M.; Percec, V.Neopentylglycolborylation of aryl chlorides catalyzed by the mixed ligand system NiCl2(dppp)/dppf,Org. Lett.2009,11,4974-4977.
[124] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Leowanawat, P.; Resmerita, A.-M.; Liu, C.;Rosen, B. M.; Percec, V. Neopentylglycolborylation of ortho-substituted aryl halides catalyzed byNiCl2-based mixed-ligand systems, J. Org. Chem.2010,75,5438-5452.
[125] Wilson, D. A.; Wilson, C. J.; Moldoveanu, C.; Resmerita, A.-M.; Corcoran, P.; Hoang, L. M.;Rosen, B. M.; Percec, V. Neopentylglycolborylation of aryl mesylates and tosylates catalyzed byNi-based mixed-ligand systems activated with Zn, J. Am. Chem. Soc.2010,132,1800-1801.
[126] Leowanawat, P.; Resmerita, A.-M.; Moldoveanu, C.; Liu, C.; Zhang, N.; Wilson, D. A.; Hoang,L. M.; Rosen, B. M.; Percec, V. Zero-valent metals accelerate the neopentylglycolborylation of arylhalides catalyzed by NiCl2-based mixed-ligand systems, J. Org. Chem.2010,75,7822-7828.
[1] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[2] Witkowski, J. T.; Robins, R. K.; Khare, G. P.; Sidwell, R. W. Synthesis and antiviral activity of1,2,4-triazole-3-thiocarboxamide and1,2,4-triazole-3-carboxamidine ribonucleosides, J. Med. Chem.1973,16,935-937.
[3] Gish, R. G. Treating hcv with ribavirin analogues and ribavirin-like molecules, J. Antimicrob.Chemother.2006,57,8-13.
[4] Kini, G. D.; Robins, R. K.; Avery, T. L. Synthesis and antitumor activity of ribavirin imidates.New facile synthesis of ribavirin amidine (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamidinehydrochloride), J. Med. Chem.1989,32,1447-1449.
[5] Gabrielsen, B.; Phelan, M. J.; Barthel-Rosa, L.; See, C.; Huggins, J. W.; Kefauver, D. F.; Monath,T. P.; Ussery, M. A.; Chmurny, G. N.; et al. Synthesis and antiviral evaluation ofn-carboxamidine-substituted analogs of1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamidinehydrochloride, J. Med. Chem.1992,35,3231-3238.
[6] Kumarapperuma, S. C.; Sun, Y.; Jeselnik, M.; Chung, K.; Parker, W. B.; Jonsson, C. B.; Arterburn,J. B. Structural effects on the phosphorylation of3-substituted1-β-d-ribofuranosyl-1,2,4-triazoles byhuman adenosine kinase, Bioorg. Med. Chem. Lett.2007,17,3203-3207.
[7] De Francesco, R.; Migliaccio, G. Challenges and successes in developing new therapies forhepatitis c, Nature (London, U. K.)2005,436,953-960.
[8] Loakes, D. The applications of universal DNA base analogues, Nucleic Acids Res.2001,29,2437-2447.
[9] Feld, J. J.; Hoofnagle, J. H. Mechanism of action of interferon and ribavirin in treatment ofhepatitis c, Nature (London, U. K.)2005,436,967-972.
[10] Wu, Q.; Qu, F.; Wan, J.; Zhu, X.; Xia, Y.; Peng, L. Design, synthesis, and characterization ofphotolabeling probes for the study of the mechanisms of the antiviral effects of ribavirin, Helv. Chim.Acta2004,87,811-819.
[11] Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Synthesis of5-aryltriazoleribonucleosides via suzuki coupling and promoted by microwave irradiation, Tetrahedron Lett.2006,47,6727-6731.
[12] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[13] Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L. Arylethynyltriazole acyclonucleosidesinhibit hepatitis c virus replication, Bioorg. Med. Chem. Lett.2008,18,3321-3327.
[14] Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Discovery of novel arylethynyltriazole ribonucleosides with selective and effective antiviral andantiproliferative activity, J. Med. Chem.2009,52,1144-1155.
[15] Xia, Y.; Liu, Y.; Wan, J.; Wang, M.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. Novel triazoleribonucleoside down-regulates heat shock protein27and induces potent anticancer activity ondrug-resistant pancreatic cancer, J. Med. Chem.2009,52,6083-6096.
[16] Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.; Peng, L. Synthesis of bitriazolylnucleosides and unexpectedly different reactivity of azidotriazole nucleoside isomers in the huisgenreaction, Org. Biomol. Chem.2007,5,1695-1701.
[17] Li, W.; Xia, Y.; Fan, Z.; Qu, F.; Wu, Q.; Peng, L. Bitriazolyl acyclonucleosides with antiviralactivity against tobacco mosaic virus, Tetrahedron Lett.2008,49,2804-2809.
[18] Xia, Y.; Wang, M.; Demaria, O.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna Juan, L.; Alexopoulou, L.;Peng, L. A novel bitriazolyl acyclonucleoside endowed with dual antiproliferation andimmunomodulatory activity, J. Med. Chem.2012, DOI:10.1021/jm300534u.
[19] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective n-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[20] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[21] Liu, Y.; Xia, Y.; Li, W.; Cong, M.; Maggiani, A.; Leyssen, P.; Qu, F.; Neyts, J.; Peng, L.S-aryltriazole acyclonucleosides: Synthesis and biological evaluation against hepatitis c virus, Bioorg.Med. Chem. Lett.2010,20,3610-3613.
[22] Xia, Y.; Liu, Y.; Rocchi, P.; Wang, M.; Fan, Y.; Qu, F.; Iovanna, J. L.; Peng, L. Targeting heatshock factor1with a triazole nucleoside analog to elicit potent anticancer activity on drug-resistantpancreatic cancer, Cancer Lett.2012,318,145-153.
[23] Peng, L.; Rocchi, P.; Iovanna, J.; Xia, Y.; Qu, F.; Wan, J.; Liu, Y.; Wang, M.; Novel triazolenucleoside derivatives, their preparation and their application in therapeutics. PCT/EP2009/055213.WO/2009/133147. Neyts, J.; Peng, L.; Qu, F.; Zhu, R.; Novel viral replication inhibitors,PCT/BE2008/000059. WO/2009/015446.
[24] Perreux, L.; Loupy, A. A tentative rationalization of microwave effects in organic synthesisaccording to the reaction medium, and mechanistic considerations, Tetrahedron2001,57,9199-9223.
[25] Kappe, C. O. Synthetic methods. Controlled microwave heating in modern organic synthesis,Angew. Chem. Int. Ed.2004,43,6250-6284.
[26] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination,Angew. Chem., Int. Ed.2008,47,6338-6361.
[27] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenuesfor modifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[28] Champeil, E.; Pradhan, P.; Lakshman, M. K. Palladium-catalyzed synthesis of nucleosideadducts from bay-and fjord-region diol epoxides, J. Org. Chem.2007,72,5035-5045.
[29] Fischer, C.; Koenig, B. Palladium-and copper-mediated n-aryl bond formation reactions for thesynthesis of biological active compounds, Beilstein J. Org. Chem.2011,7,59-74, No10.
[30] Reetz, M. T. Combinatorial transition-metal catalysis: Mixing monodentate ligands to controlenantio-, diastero-, and regioselectivity, Angew. Chem. Int. Ed.2008,47,2556-2588.
[31] Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Simple mixedtricyclohexylphosphane-triarylphosphite complexes as extremely high-activity catalysts for the Suzukicoupling of aryl chlorides, Angew. Chem. Int. Ed.2002,41,4120-4122.
[32] Fors, B. P.; Buchwald, S. L. A multiligand based Pd catalyst for C-N cross-coupling reactions, J.Am. Chem. Soc.2010,132,15914-15917.
[33] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Corcoran, P.; Rosen, B. M.; Percec, V.Neopentylglycolborylation of aryl chlorides catalyzed by the mixed ligand system NiCl2(dppp)/dppf,Org. Lett.2009,11,4974-4977.
[34] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Leowanawat, P.; Resmerita, A.-M.; Liu, C.; Rosen,B. M.; Percec, V. Neopentylglycolborylation of ortho-substituted aryl halides catalyzed by NiCl2-basedmixed-ligand systems, J. Org. Chem.2010,75,5438-5452.
[35] Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. NiCl2(dppe)-catalyzed cross-coupling ofaryl mesylates, arenesulfonates, and halides with arylboronic acids, J. Org. Chem.2004,69,3447-3452.
[1] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective N-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[2] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[3]李蔚，武汉大学博士论文，"1,2,4-三氮唑开环核苷型抗病毒药物先导物的设计、合成、表征及筛选"，2009.
[4] Kappe, C. O. Synthetic methods. Controlled microwave heating in modern organic synthesis,Angew. Chem. Int. Ed.2004,43,6250-6284.
[5] Kappe, C. O.; Dallinger, D. The impact of microwave synthesis on drug discovery, Nat. Rev. DrugDiscovery2006,5,51-63.
[6] Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Synthesis of5-aryltriazoleribonucleosides via Suzuki coupling and promoted by microwave irradiation, Tetrahedron Lett.2006,47,6727-6731.
[7] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[8] Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L. Arylethynyltriazole acyclonucleosidesinhibit hepatitis c virus replication, Bioorg. Med. Chem. Lett.2008,18,3321-3327.
[9] Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Discovery of novel arylethynyltriazole ribonucleosides with selective and effective antiviral andantiproliferative activity, J. Med. Chem.2009,52,1144-1155.
[10] Chen, S.; Huang, H.; Liu, X.; Shen, J.; Jiang, H.; Liu, H. Microwave-assisted efficientcopper-promoted N-arylation of amines with arylboronic acids, J. Comb. Chem.2008,10,358-360.
[1] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective N-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[2] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[3] Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification ofaryl halides, Acc. Chem. Res.2008,41,1534-1544.
[4] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination, Angew.Chem., Int. Ed.2008,47,6338-6361.
[5] Khalafi-Nezhad, A.; Zare, A.; Parhami, A.; Rad, M. N. S.; Nejabat, G. R. RegioselectiveN-arylation of some pyrimidine and purine nucleobases, Synth. Commun.2006,36,3549-3562.
[6] Fischer, C.; Koenig, B. Palladium-and copper-mediated N-aryl bond formation reactions for thesynthesis of biological active compounds, Beilstein J. Org. Chem.2011,7,59-74, No10.
[7] Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. Palladium-catalyzed C-N bondformation: Facile and general synthesis of N6-aryl2'-deoxyadenosine analogues, J. Am. Chem. Soc.1999,121,6090-6091.
[8] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenues formodifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[9] Thomson, P. F.; Lagisetty, P.; Balzarini, J.; De Clercq, E.; Lakshman, M. K. Palladium-catalyzedaryl amination reactions of6-bromo-and6-chloropurine nucleosides, Adv. Synth. Catal.2010,352,1728-1735.
[10] Pratap, R.; Parrish, D.; Gunda, P.; Venkataraman, D.; Lakshman, M. K. Influence of biarylphosphine structure on C-N and C-C bond formation, J. Am. Chem. Soc.2009,131,12240-12249.
[11] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[12] Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Synthesis of5-aryltriazoleribonucleosides via suzuki coupling and promoted by microwave irradiation, Tetrahedron Lett.2006,47,6727-6731.
[13] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[14] Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L. Arylethynyltriazole acyclonucleosidesinhibit hepatitis C virus replication, Bioorg. Med. Chem. Lett.2008,18,3321-3327.
[15] Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Discovery of novel arylethynyltriazole ribonucleosides with selective and effective antiviral andantiproliferative activity, J. Med. Chem.2009,52,1144-1155.
[16]朱瑞芝，武汉大学博士论文，"新型1,2,4-三氮唑开环核苷衍生物的设计、合成及表征"，2007.
[17] Chakraborti, D.; Colis, L.; Schneider, R.; Basu, A. K. Synthesis of n22'-deoxyguanosine adductsformed by1-nitropyrene, Org. Lett.2003,5,2861-2864.
[18] Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.; Peng, L. Synthesis of bitriazolylnucleosides and unexpectedly different reactivity of azidotriazole nucleoside isomers in the huisgenreaction, Org. Biomol. Chem.2007,5,1695-1701.
[19] Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Bite angle effects of diphosphines in c-cand c-x bond forming cross coupling reactions, Chem. Soc. Rev.2009,38,1099-1118.
[20] Fujita, K.-i.; Yamashita, M.; Puschmann, F.; Martinez Alvarez-Falcon, M.; Incarvito, C. D.;Hartwig, J. F. Organometallic chemistry of amidate complexes. Accelerating effect of bidentate ligandson the reductive elimination of N-aryl amidates from palladium(ii), J. Am. Chem. Soc.2006,128,9044-9045.
[21] Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Wide bite angle diphosphines:Xantphos ligands in transition metal complexes and catalysis, Acc. Chem. Res.2001,34,895-904.
[22] Jeulin, S.; De Paule, S. D.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P.Chiral biphenyl diphosphines for asymmetric catalysis: Stereoelectronic design and industrialperspectives, Proc. Natl. Acad. Sci.2004,101,5799-5804.
[23] van Zeist, W.-J.; Visser, R.; Bickelhaupt, F. M. The steric nature of the bite angle, Chem.--Eur. J.2009,15,6112-6115.
[24] Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L. Ligand-mediated highlyeffective and selective C-N coupling for synthesizing bioactive N-aryltriazole acyclonucleosides, Org.Lett.2010,12,5712-5715.
[1] Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L. Ligand-mediated highlyeffective and selective C-N coupling for synthesizing bioactive n-aryltriazole acyclonucleosides, Org.Lett.2010,12,5712-5715.
[2] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[3] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[4] Fors, B. P.; Buchwald, S. L. A multiligand based Pd catalyst for C-N cross-coupling reactions, J.Am. Chem. Soc.2010,132,15914-15917.
[5] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[6] Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. Palladium-catalyzed C-N bondformation: Facile and general synthesis of N6-aryl2'-deoxyadenosine analogues, J. Am. Chem. Soc.1999,121,6090-6091.
[7] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenues formodifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[8] Thomson, P. F.; Lagisetty, P.; Balzarini, J.; De Clercq, E.; Lakshman, M. K. Palladium-catalyzedaryl amination reactions of6-bromo-and6-chloropurine nucleosides, Adv. Synth. Catal.2010,352,1728-1735.
[9] Klingensmith, L. M.; Strieter, E. R.; Barder, T. E.; Buchwald, S. L. New insights intoXantphos/Pd-catalyzed C-N bond forming reactions: A structural and kinetic study, Organometallics2006,25,82-91.
[10] Amatore, C.; Jutand, A.; Thuilliez, A. Formation of palladium(0) complexes from Pd(OAc)2anda bidentate phosphine ligand (dppp) and their reactivity in oxidative addition, Organometallics2001,20,3241-3249.
[11] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination, Angew.Chem., Int. Ed.2008,47,6338-6361.
[12] Fan, Y.; Xia, Y.; Tang, J.; Ziarelli, F.; Qu, F.; Rocchi, P.; Iovanna, J. L.; Peng, L. An efficientmixed-ligand Pd catalytic system to promote C-N coupling for the synthesis of N-arylaminotriazolenucleosides, Chem.--Eur. J.2012,18,2221-2225.
[1] Sidwell, R. W.; Huffman, J. H.; Khare, G. P.; Allen, L. B.; Witkowski, J. T.; Robins, R. K.Broad-spectrum antiviral activity of virazole.1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide,Science1972,177,705-706.
[2] Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J. L. Pancreatic cancer, Lancet2004,363,1049-1057.
[3] Pierantoni, C.; Pagliacci, A.; Scartozzi, M.; Berardi, R.; Bianconi, M.; Cascinu, S. Pancreaticcancer: Progress in cancer therapy, Crit Rev Oncol Hematol2008,67,27-38.
[4] Rivera, F.; Lopez-Tarruella, S.; Vega-Villegas, M. E.; Salcedo, M. Treatment of advancedpancreatic cancer: From gemcitabine single agent to combinations and targeted therapy, Cancer Treat.Rev.2009,35,335-339.
[5] Berlin, J.; Benson, A. B., III Gemcitabine remains the standard of care for pancreatic cancer, Nat.Rev. Clin. Oncol.2010,7,135-137.
[6] Mukherji, D.; Pezaro, C. J.; De-Bono, J. S. For the treatment of prostate cancer, Expert Opin.Invest. Drugs2012,21,227-233.
[7]王孟华，武汉大学博士论文，"新型1,2,4-三氮唑核苷的合成及其生物活性研究"，2009
[8] Xia, Y.; Liu, Y.; Rocchi, P.; Wang, M.; Fan, Y.; Qu, F.; Iovanna, J. L.; Peng, L. Targeting heatshock factor1with a triazole nucleoside analog to elicit potent anticancer activity on drug-resistantpancreatic cancer, Cancer Lett.2012,318,145-153.
[9] Fan, Y.; Xia, Y.; Tang, J.; Ziarelli, F.; Qu, F.; Rocchi, P.; Iovanna, J. L.; Peng, L. An efficientmixed-ligand Pd catalytic system to promote C-N coupling for the synthesis of N-arylaminotriazolenucleosides, Chem.--Eur. J.2012,18,2221-2225.
[10] Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L. Ligand-mediated highlyeffective and selective C-N coupling for synthesizing bioactive N-aryltriazole acyclonucleosides, Org.Lett.2010,12,5712-5715.
[2] Jordheim, L. P.; Dumontet, C. Review of recent studies on resistance to cytotoxicdeoxynucleoside analogues, Biochim. Biophys. Acta, Rev.2007,1776,138-159.
[3] Ewald, B.; Sampath, D.; Plunkett, W. Nucleoside analogs: Molecular mechanisms signaling celldeath, Oncogene2008,27,6522-6537.
[4] Herdewijn, P.; Editor Modified nucleosides in biochemistry, biotechnology and medicine;WILEY-VCH Verlag GmbH&Co. KGaA:Weinheim, Germany,2008.
[5] Galmarini, C. M.; Popowycz, F.; Joseph, B. Cytotoxic nucleoside analogues: Different strategiesto improve their clinical efficacy, Curr. Med. Chem.2008,15,1072-1082.
[6] Claire, S. Nucleoside mimetics: Their chemistry and biological properties, Advanced ChemistryTexts, Gordon and Beach Science Publishers, UK,2001.
[7] De Clercq, E. Antiviral drugs: Current state of the art, J. Clin. Virol.2001,22,73-89.
[8] De Clercq, E. Antiviral drugs in current clinical use, J. Clin. Virol.2004,30,115-133.
[9] De Clercq, E.; Holy, A. Acyclic nucleoside phosphonates: A key class of antiviral drugs, Nat RevDrug Discov2005,4,928-940.
[10] De Clercq, E. The design of drugs for hiv and hcv, Nat. Rev. Drug Discovery2007,6,1001-1018.
[11] Schaeffer, H. J.; Beauchamp, L.; De Miranda, P.; Elion, G. B.; Bauer, D. J.; Collins, P.9-(2-hydroxyethoxymethyl)guanine activity against viruses of the herpes group, Nature1978,272,583-585.
[12] Sidwell, R. W.; Huffman, J. H.; Khare, G. P.; Allen, L. B.; Witkowski, J. T.; Robins, R. K.Broad-spectrum antiviral activity of virazole.1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide,Science1972,177,705-706.
[13] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[14] Galmarini, C. M.; Mackey, J. R.; Dumontet, C. Nucleoside analogues and nucleobases in cancertreatment, Lancet Oncol.2002,3,415-424.
[15] Witkowski, J. T.; Robins, R. K.; Sidwell, R. W.; Simon, L. N. Design, synthesis, and broadspectrum antiviral activity of1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides,J. Med. Chem.1972,15,1150-1154.
[16] Streeter, D. G.; Witkowski, J. T.; Khare, G. P.; Sidwell, R. W.; Bauer, R. J.; Robins, R. K.; Simon,L. N. Mechanism of action of1-β-d-ribofuranosyl-1'2,4-triazole-3-carboxamide (virazole), a newbroad-spectrum antiviral agent, Proc. Nat. Acad. Sci. U. S. A. FIELD Full Journal Title:Proceedings ofthe National Academy of Sciences of the United States of America1973,70,1174-1178.
[17] De Clercq, E. Strategies in the design of antiviral drugs, Nat. Rev. Drug Discovery2002,1,13-25.
[18] Assouline, S.; Culjkovic, B.; Cocolakis, E.; Rousseau, C.; Beslu, N.; Amri, A.; Caplan, S.; Leber,B.; Roy, D.-C.; Miller, W. H., Jr.; Borden, K. L. B. Molecular targeting of the oncogene eif4e in acutemyeloid leukemia (aml): A proof-of-principle clinical trial with ribavirin, Blood2009,114,257-260.
[19] Borden, K. L. B.; Culjkovic-Kraljacic, B. Ribavirin as an anti-cancer therapy: Acute myeloidleukemia and beyond?, Leuk. Lymphoma2010,51,1805-1815.
[20] Graci, J. D.; Cameron, C. E. Quasispecies, error catastrophe, and the antiviral activity ofribavirin, Virology2002,298,175-180.
[21] Crotty, S.; Maag, D.; Arnold, J. J.; Zhong, W.; Lau, J. Y. N.; Hong, Z.; Andino, R.; Cameron, C.E. The broad-spectrum antiviral ribonucleoside ribavirin is an rna virus mutagen, Nat. Med.2000,6,1375-1379.
[22] Crotty, S.; Cameron, C. E.; Andino, R. Rna virus error catastrophe: Direct molecular test byusing ribavirin, Proc. Natl. Acad. Sci. U. S. A.2001,98,6895-6900.
[23] Davis, G. L.; Esteban-Mur, R.; Rustgi, V.; Hoefs, J.; Gordon, S. C.; Trepo, C.; Shiffman, M. L.;Zeuzem, S.; Craxi, A.; Ling, M.-H.; Albrecht, J. Interferon alfa-2b alone or in combination withribavirin for the treatment of relapse of chronic hepatitis c, N. Engl. J. Med.1998,339,1493-1499.
[24] Berlin, J.; Benson, A. B., III Gemcitabine remains the standard of care for pancreatic cancer, Nat.Rev. Clin. Oncol.2010,7,135-137.
[25] Pierantoni, C.; Pagliacci, A.; Scartozzi, M.; Berardi, R.; Bianconi, M.; Cascinu, S. Pancreaticcancer: Progress in cancer therapy, Crit Rev Oncol Hematol2008,67,27-38.
[26] Huang, P.; Plunkett, W. Induction of apoptosis by gemcitabine, Semin. Oncol.1995,22,19-25.
[27] Rivera, F.; Lopez-Tarruella, S.; Vega-Villegas, M. E.; Salcedo, M. Treatment of advancedpancreatic cancer: From gemcitabine single agent to combinations and targeted therapy, Cancer Treat.Rev.2009,35,335-339.
[28] Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J. L. Pancreatic cancer, Lancet2004,363,1049-1057.
[29] http://www.pharmgkb.org/images/pathway/gemcitabine.png
[30] Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chemical synthesis of heterocyclic-sugarnucleoside analogues, Chem. Rev.2010,110,3337-3370.
[31] Claire, S. Nucleoside mimetics: Their chemistry and biologicalproperties, Advanced Chemistry Texts, Gordon and Beach Science Publishers, UK,2001.
[32] Minakawa, N.; Takeda, T.; Sasaki, T.; Matsuda, A.; Ueda, T. Nucleosides and nucleotides.96.Synthesis and antitumor activity of5-ethynyl-1-β-d-ribofuranosylimidazole-4-carboxamide (eicar) andits derivatives, J. Med. Chem.1991,34,778-786.
[33] Yin, M.-b.; Rustum, Y. M. Comparative DNA strand breakage induced by fura and fdurd inhuman ileocecal adenocarcinoma (hct-8) cells: Relevance to cell growth inhibition, Cancer Commun.1991,3,45-51.
[34] Robins, M. J.; Barr, P. J. Nucleic acid related compounds.39. Efficient conversion of5-iodo to5-alkynyl and derived5-substituted uracil bases and nucleosides, J. Org. Chem.1983,48,1854-1862.
[35] Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C. D.; Clark, C. G.;Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler,R. R. Discovery of1-(3'-aminobenzisoxazol-5'-yl)-3-trifluoromethyl-n-[2-fluoro-4-
[(2'-dimethylaminomethyl) imidazol-1-yl]phenyl]-1h-pyrazole-5-carboxyamide hydrochloride(razaxaban), a highly potent, selective, and orally bioavailable factor xa inhibitor, J. Med. Chem.2005,48,1729-1744.
[36] Comprehensive Heterocyclic Chemistry II; Katritzky, A.R., Rees, C.W.,Eds.; Elsevier: Oxford,1996;
[37] http://www.drugs.com/top200.html
[38] http://www.drugs.com/top200.html
[39] Evano, G.; Blanchard, N.; Toumi, M. Copper-mediated coupling reactions and their applicationsin natural products and designed biomolecules synthesis, Chem. Rev.2008,108,3054-3131.
[40] Fischer, C.; Koenig, B. Palladium-and copper-mediated N-aryl bond formation reactions for thesynthesis of biological active compounds, Beilstein J. Org. Chem.2011,7,59-74, No10.
[41] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination,Angew. Chem., Int. Ed.2008,47,6338-6361.
[42] Rosemeyer, H. The chemodiversity of purine as a constituent of natural products, ChemBiodivers2004,1,361-401.
[43] Legraverend, M. Recent advances in the synthesis of purine derivatives and their precursors,Tetrahedron2008,64,8585-8603.
[44] Jacobson, K. A.; Van Galen, P. J. M.; Williams, M. Adenosine receptors: Pharmacology,structure-activity relationships, and therapeutic potential, J. Med. Chem.1992,35,407-422.
[45] Miller, C. O. Kinetin and related compounds in plant growth, Annu. Rev. Plant Physiol.1961,12,395-408.
[46] Brathe, A.; Gundersen, L.-L.; Rise, F.; Eriksen, A. B.; Vollsnes, A. V.; Wang, L. Synthesis of6-alkenyl-and6-alkynylpurines with cytokinin activity, Tetrahedron1999,55,211-228.
[47] Montgomery, J. A.; Hewson, K. Analogs of6-methyl-9β-d-ribofuranosylpurine, J. Med. Chem.1968,11,48-52.
[48] Wright, G. E.; Dudycz, L. W. Synthesis and characterization of N2-(p-n-butylphenyl)-2'-deoxyguanosine and its5'-triphosphate and their inhibition of hela DNA polymerase, J. Med.Chem.1984,27,175-181.
[49] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective N-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[50] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[51] Ullmann, F.; Bielecki, J. Synthesis in the biphenyl series. I, Ber. Dtsch. Chem. Ges.1901,34,2174-2185.
[52] Ullmann, F. A new path for preparing diphenylamine derivatives, Ber. Dtsch. Chem. Ges.1903,36,2382-2384.
[53] Goldberg, I. Phenylation in the presence of copper as catalyst, Ber. Dtsch. Chem. Ges.1906,39,1691-1692.
[54] Monnier, F.; Taillefer, M. Catalytic C-C, C-N, and C-O ullmann-type coupling reactions: Coppermakes a difference, Angew. Chem., Int. Ed.2008,47,3096-3099.
[55] Ullmann, F.; Sponagel, P. Phenylation of phenols, Ber. Dtsch. Chem. Ges.1905,38,2211-2212.
[56] Ley, S. V.; Thomas, A. W. Modern synthetic methods for copper-mediated C(aryl)-O, C(aryl)-N,and C(aryl)-S bond formation, Angew. Chem., Int. Ed.2003,42,5400-5449.
[57] Kunz, K.; Scholz, U.; Ganzer, D. Renaissance of ullmann and goldberg reactions-progress incopper catalyzed C-N-, C-O and C-S coupling, Synlett2003,2428-2439.
[58] Monnier, F.; Taillefer, M. Catalytic C-C, C-N, and C-O ullmann-type coupling reactions, Angew.Chem., Int. Ed.2009,48,6954-6971.
[59] Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. Accelerating effect induced by the structure of-amino acid in the copper-catalyzed coupling reaction of aryl halides with-amino acids. Synthesis ofbenzolactam-v8, J. Am. Chem. Soc.1998,120,12459-12467.
[60] Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. An efficient copper-catalyzed coupling of arylhalides with imidazoles, Tetrahedron Lett.1999,40,2657-2660.
[61] Goodbrand, H. B.; Hu, N.-X. Ligand-accelerated catalysis of the ullmann condensation:Application to hole conducting triarylamines, J. Org. Chem.1999,64,670-674.
[62] Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. Using intelligent/random libraryscreening to design focused libraries for the optimization of homogeneous catalysts: Ullmann etherformation, J. Am. Chem. Soc.2000,122,5043-5051.
[63] Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Highly efficient and mildcopper-catalyzed N-and C-arylations with aryl bromides and iodides, Chem.--Eur. J.2004,10,5607-5622.
[64] Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Mild conditions for copper-catalyzedN-arylation of pyrazoles, Eur. J. Org. Chem.2004,695-709.
[65] Ma, D.; Cai, Q. L-proline-promoted ullmann-type coupling reactions of aryl iodides with indoles,pyrroles, imidazoles or pyrazoles, Synlett2004,128-130.
[66] Cai, Q.; Zhu, W.; Zhang, H.; Zhang, Y.; Ma, D. Preparation of N-aryl compounds by aminoacid-promoted ullmann-type coupling reactions, Synthesis2005,496-499.
[67] Zhang, H.; Cai, Q.; Ma, D. Amino acid promoted Cu-catalyzed C-N bond formation betweenaryl halides and amines or N-containing heterocycles, J. Org. Chem.2005,70,5164-5173.
[68] Antilla, J. C.; Klapars, A.; Buchwald, S. L. The copper-catalyzed N-arylation of indoles, J. Am.Chem. Soc.2002,124,11684-11688.
[69] Altman, R. A.; Buchwald, S. L.4,7-dimethoxy-1,10-phenanthroline: An excellent ligand for theCu-catalyzed N-arylation of imidazoles, Org. Lett.2006,8,2779-2782.
[70] Altman, R. A.; Koval, E. D.; Buchwald, S. L. Copper-catalyzed N-arylation of imidazoles andbenzimidazoles, J. Org. Chem.2007,72,6190-6199.
[71] Zhu, R.; Xing, L.; Wang, X.; Cheng, C.; Su, D.; Hu, Y. Highly practical "Ligand-free-like"Copper-catalyzed N-arylation of azoles in lower nitrile solvents, Adv. Synth. Catal.2008,350,1253-1257.
[72] Tao, C. Z.; Li, J.; Cui, X.; Fu, Y.; Guo, Q. X. Cu-catalyzed cross-couplings under ligandlessconditions, Chin. Chem. Lett.2007,18,1199-1202.
[73] Li, J. J. In Name Reactions: A Collection of Detailed Reaction Mechanisms and SyntheticApplications,4th ed.; Springer: New York,2009,102.
[74] Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.New aryl/heteroaryl C-N bond cross-coupling reactions via arylboronic acid/cupric acetate arylation,Tetrahedron Lett.1998,39,2941-2944.
[75] Lam, P. Y. S.; Clark, C. G.; Li, R.; Pinto, D. J. P.; Orwat, M. J.; Galemmo, R. A.; Fevig, J. M.;Teleha, C. A.; Alexander, R. S.; Smallwood, A. M.; Rossi, K. A.; Wright, M. R.; Bai, S. A.; He, K.;Luettgen, J. M.; Wong, P. C.; Knabb, R. M.; Wexler, R. R. Structure-based design of novelguanidine/benzamidine mimics: Potent and orally bioavailable factor Xa inhibitors as novelanticoagulants, J. Med. Chem.2003,46,4405-4418.
[76] Chan, D. M. T.; Monaco, K. L.; Li, R.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Copper promotedC-N and C-O bond cross-coupling with phenyl and pyridylboronates, Tetrahedron Lett.2003,44,3863-3865.
[77] Singh, B. K.; Appukkuttan, P.; Claerhout, S.; Parmar, V. S.; Van der Eycken, E.Copper(ii)-mediated cross-coupling of arylboronic acids and2(1H)-pyrazinones facilitated bymicrowave irradiation with simultaneous cooling, Org. Lett.2006,8,1863-1866.
[78] Bekolo, H. Copper-mediated N-arylation of electron-deficient pyrroles and indoles, Can. J.Chem.2007,85,42-46.
[79] Wang, W.; Devasthale, P.; Farrelly, D.; Gu, L.; Harrity, T.; Cap, M.; Chu, C.; Kunselman, L.;Morgan, N.; Ponticiello, R.; Zebo, R.; Zhang, L.; Locke, K.; Lippy, J.; O'Malley, K.; Hosagrahara, V.;Zhang, L.; Kadiyala, P.; Chang, C.; Muckelbauer, J.; Doweyko, A. M.; Zahler, R.; Ryono, D.;Hariharan, N.; Cheng, P. T. W. Discovery of azetidinone acids as conformationally-constrained dualppar/γ agonists, Bioorg. Med. Chem. Lett.2008,18,1939-1944.
[80] Sreeramamurthy, K.; Ashok, E.; Mahendar, V.; Santoshkumar, G.; Das, P. Direct synthesis ofn-aryl derivatives of quinazolin-4(3h)-ones employing arylboronic acids in the presence of Cu(OAc)2,Synlett2011,721-724.
[81] Harmse, L.; van Zyl, R.; Gray, N.; Schultz, P.; Leclerc, S.; Meijer, L.; Doerig, C.; Havlik, I.Structure-activity relationships and inhibitory effects of various purine derivatives on the in vitrogrowth of plasmodium falciparum, Biochem. Pharmacol.2001,62,341-348.
[82] Meijer, L.; Raymond, E. Roscovitine and other purines as kinase inhibitors. From starfishoocytes to clinical trials, Acc. Chem. Res.2003,36,417-425.
[83] Strouse, J. J.; Jegelnik, M.; Arterburn, J. B. Applications of boronic acids in selective C-C andC-N arylation of purines, Acta Chim. Slov.2005,52,187-199.
[84] Khalafi-Nezhad, A.; Zare, A.; Parhami, A.; Rad, M. N. S.; Nejabat, G. R. Regioselectiven-arylation of some pyrimidine and purine nucleobases, Synth. Commun.2006,36,3549-3562.
[85] Strouse, J. J.; Jeselnik, M.; Tapaha, F.; Jonsson, C. B.; Parker, W. B.; Arterburn, J. B. Coppercatalyzed arylation with boronic acids for the synthesis of N1-aryl purine nucleosides, Tetrahedron Lett.2005,46,5699-5702.
[86] Bakkestuen, A. K.; Gundersen, L.-L. Regioselective N-9arylation of purines employingarylboronic acids in the presence of Cu(ii), Tetrahedron Lett.2003,44,3359-3362.
[87] Yue, Y.; Zheng, Z.-G.; Wu, B.; Xia, C.-Q.; Yu, X.-Q. Copper-catalyzed cross-coupling reactionsof nucleobases with arylboronic acids: An efficient access to n-aryl nucleobases, Eur. J. Org. Chem.2005,5154-5157.
[88] Guram, A. S.; Rennels, R. A.; Buchwald, S. L. A simple catalytic method for the conversion ofaryl bromides to arylamines, Angew. Chem., Int. Ed.1995,34,1348-1350.
[89] Louie, J.; Hartwig, J. F. Palladium-catalyzed synthesis of arylamines from aryl halides.Mechanistic studies lead to coupling in the absence of tin reagents, Tetrahedron Lett.1995,36,3609-3612.
[90] Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. Insights into the origin of high activity andstability of catalysts derived from bulky, electron-rich monophosphinobiaryl ligands in thepd-catalyzed c-n bond formation, J. Am. Chem. Soc.2003,125,13978-13980.
[91] Muci, A. R.; Buchwald, S. L. Practical palladium catalysts for C-N and C-O bond formation,Top. Curr. Chem.2002,219,131-209.
[92] Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherificationof aryl halides, Acc. Chem. Res.2008,41,1534-1544.
[93] Kosugi, M.; Kameyama, M.; Migita, T. Palladium-catalyzed aromatic amination of arylbromides with N,N-diethylaminotributyltin, Chem. Lett.1983,927-928.
[94] Guram, A. S.; Buchwald, S. L. Palladium-catalyzed aromatic aminations with in situ generatedaminostannanes, J. Am. Chem. Soc.1994,116,7901-7902.
[95] Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. An improved catalyst system for aromaticcarbon-nitrogen bond formation: The possible involvement of bis(phosphine) palladium complexes askey intermediates, J. Am. Chem. Soc.1996,118,7215-7216.
[96] Driver, M. S.; Hartwig, J. F. A second-generation catalyst for aryl halide amination: Mixedsecondary amines from aryl halides and primary amines catalyzed by (dppf)PdCl2, J. Am. Chem. Soc.1996,118,7217-7218.
[97] Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Bite angle effects of diphosphines in C-Cand C-X bond forming cross coupling reactions, Chem. Soc. Rev.2009,38,1099-1118.
[98] Strieter, E. R.; Buchwald, S. L. Evidence for the formation and structure of palladacycles duringPd-catalyzed C-N bond formation with catalysts derived from bulky monophosphinobiaryl ligands,Angew. Chem. Int. Ed.2006,45,925-928.
[99] Phan, N. T. S.; Van Der Sluys, M.; Jones, C. W. On the nature of the active species in palladiumcatalyzed mizoroki-heck and suzuki-miyaura couplings-homogeneous or heterogeneous catalysis, acritical review, Adv. Synth. Catal.2006,348,609-679.
[100] Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. Structural insights into active catalyst structuresand oxidative addition to (biaryl)phosphine-palladium complexes via density functional theory andexperimental studies, Organometallics2007,26,2183-2192.
[101] Barder, T. E.; Buchwald, S. L. Insights into amine binding to biaryl phosphine palladiumoxidative addition complexes and reductive elimination from biaryl phosphine arylpalladium amidocomplexes via density functional theory, J. Am. Chem. Soc.2007,129,12003-12010.
[102] M. Beller, A. Zapf, Palladium-Catalyzed Coupling Reactions for Industrial Fine ChemicalsSyntheses, in: Handbook of Organopalladium Chemistry for Organic Synthesis, Vol.1,(Ed.: E.-i.Negishi), Wiley, New York,2002, p.1209
[103] Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.; Dingerdissen, U.;Beller, M. New ligands for a general palladium-catalyzed amination of aryl and heteroaryl chlorides,Chem.--Eur. J.2004,10,2983-2990.
[104] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenuesfor modifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[105] Wagaw, S.; Buchwald, S. L. The synthesis of aminopyridines: A method employingpalladium-catalyzed carbon-nitrogen bond formation, J. Org. Chem.1996,61,7240-7241.
[106] Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. Palladium-catalyzed C-N bondformation: Facile and general synthesis of n6-aryl2'-deoxyadenosine analogues, J. Am. Chem. Soc.1999,121,6090-6091.
[107] De Riccardis, F.; Bonala, R. R.; Johnson, F. A general method for the synthesis of the N2-andN6-carcinogenic amine adducts of2'-deoxyguanosine and2'-deoxyadenosine, J. Am. Chem. Soc.1999,121,10453-10460.
[108] Riccardis, F. D.; Johnson, F. Chemical synthesis of cross-linked purine nucleosides, Org. Lett.2000,2,293-295.
[109] Pratap, R.; Parrish, D.; Gunda, P.; Venkataraman, D.; Lakshman, M. K. Influence of biarylphosphine structure on C-N and C-C bond formation, J. Am. Chem. Soc.2009,131,12240-12249.
[110] Thomson, P. F.; Lagisetty, P.; Balzarini, J.; De Clercq, E.; Lakshman, M. K.Palladium-catalyzed aryl amination reactions of6-bromo-and6-chloropurine nucleosides, Adv. Synth.Catal.2010,352,1728-1735.
[111] Champeil, E.; Pradhan, P.; Lakshman, M. K. Palladium-catalyzed synthesis of nucleosideadducts from bay-and fjord-region diol epoxides, J. Org. Chem.2007,72,5035-5045.
[112] Reetz, M. T.; Sell, T.; Meiswinkel, A.; Mehler, G. A new principle in combinatorial asymmetrictransition-metal catalysis: Mixtures of chiral monodentate p ligands, Angew. Chem. Int. Ed.2003,42,790-793.
[113] Reetz, M. T. Combinatorial transition-metal catalysis: Mixing monodentate ligands to controlenantio-, diastero-, and regioselectivity, Angew. Chem. Int. Ed.2008,47,2556-2588.
[114] Reetz, M. T.; Li, X. Mixtures of configurationally stable and fluxional atropisomericmonodentate p ligands in asymmetric rh-catalyzed olefin hydrogenation, Angew. Chem. Int. Ed.2005,44,2959-2962.
[115] Reetz, M. T.; Mehler, G. Mixtures of chiral and achiral monodentate ligands in asymmetricrh-catalyzed olefin hydrogenation: Reversal of enantioselectivity, Tetrahedron Lett.2003,44,4593-4596.
[116] Pena, D.; Minnaard, A. J.; Boogers, J. A. F.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B. L.Improving conversion and enantioselectivity in hydrogenation by combining different monodentatephosphoramidites; a new combinatorial approach in asymmetric catalysis, Org. Biomol. Chem.2003,1,1087-1089.
[117] Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Simple mixedtricyclohexylphosphane-triarylphosphite complexes as extremely high-activity catalysts for the suzukicoupling of aryl chlorides, Angew. Chem. Int. Ed.2002,41,4120-4122.
[118] Fors, B. P.; Buchwald, S. L. A multiligand based Pd catalyst for C-N cross-coupling reactions, J.Am. Chem. Soc.2010,132,15914-15917.
[119] Tang, W.; Keshipeddy, S.; Zhang, Y.; Wei, X.; Savoie, J.; Patel, N. D.; Yee, N. K.; Senanayake,C. H. Efficient monophosphorus ligands for palladium-catalyzed miyaura borylation, Org. Lett.2011,13,1366-1369.
[120] Saito, S.; Oh-tani, S.; Miyaura, N. Synthesis of biaryls via a nickel(0)-catalyzed cross-couplingreaction of chloroarenes with arylboronic acids, J. Org. Chem.1997,62,8024-8030.
[121] Galland, J.-C.; Savignae, M.; Genet, J.-P. Cross-coupling of chloroarenes with boronic acidsusing a water-soluble nickel catalyst, Tetrahedron Lett.1999,40,2323-2326.
[122] Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. NiCl2(dppe)-catalyzed cross-coupling ofaryl mesylates, arenesulfonates, and halides with arylboronic acids, J. Org. Chem.2004,69,3447-3452.
[123] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Corcoran, P.; Rosen, B. M.; Percec, V.Neopentylglycolborylation of aryl chlorides catalyzed by the mixed ligand system NiCl2(dppp)/dppf,Org. Lett.2009,11,4974-4977.
[124] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Leowanawat, P.; Resmerita, A.-M.; Liu, C.;Rosen, B. M.; Percec, V. Neopentylglycolborylation of ortho-substituted aryl halides catalyzed byNiCl2-based mixed-ligand systems, J. Org. Chem.2010,75,5438-5452.
[125] Wilson, D. A.; Wilson, C. J.; Moldoveanu, C.; Resmerita, A.-M.; Corcoran, P.; Hoang, L. M.;Rosen, B. M.; Percec, V. Neopentylglycolborylation of aryl mesylates and tosylates catalyzed byNi-based mixed-ligand systems activated with Zn, J. Am. Chem. Soc.2010,132,1800-1801.
[126] Leowanawat, P.; Resmerita, A.-M.; Moldoveanu, C.; Liu, C.; Zhang, N.; Wilson, D. A.; Hoang,L. M.; Rosen, B. M.; Percec, V. Zero-valent metals accelerate the neopentylglycolborylation of arylhalides catalyzed by NiCl2-based mixed-ligand systems, J. Org. Chem.2010,75,7822-7828.
[1] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[2] Witkowski, J. T.; Robins, R. K.; Khare, G. P.; Sidwell, R. W. Synthesis and antiviral activity of1,2,4-triazole-3-thiocarboxamide and1,2,4-triazole-3-carboxamidine ribonucleosides, J. Med. Chem.1973,16,935-937.
[3] Gish, R. G. Treating hcv with ribavirin analogues and ribavirin-like molecules, J. Antimicrob.Chemother.2006,57,8-13.
[4] Kini, G. D.; Robins, R. K.; Avery, T. L. Synthesis and antitumor activity of ribavirin imidates.New facile synthesis of ribavirin amidine (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamidinehydrochloride), J. Med. Chem.1989,32,1447-1449.
[5] Gabrielsen, B.; Phelan, M. J.; Barthel-Rosa, L.; See, C.; Huggins, J. W.; Kefauver, D. F.; Monath,T. P.; Ussery, M. A.; Chmurny, G. N.; et al. Synthesis and antiviral evaluation ofn-carboxamidine-substituted analogs of1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamidinehydrochloride, J. Med. Chem.1992,35,3231-3238.
[6] Kumarapperuma, S. C.; Sun, Y.; Jeselnik, M.; Chung, K.; Parker, W. B.; Jonsson, C. B.; Arterburn,J. B. Structural effects on the phosphorylation of3-substituted1-β-d-ribofuranosyl-1,2,4-triazoles byhuman adenosine kinase, Bioorg. Med. Chem. Lett.2007,17,3203-3207.
[7] De Francesco, R.; Migliaccio, G. Challenges and successes in developing new therapies forhepatitis c, Nature (London, U. K.)2005,436,953-960.
[8] Loakes, D. The applications of universal DNA base analogues, Nucleic Acids Res.2001,29,2437-2447.
[9] Feld, J. J.; Hoofnagle, J. H. Mechanism of action of interferon and ribavirin in treatment ofhepatitis c, Nature (London, U. K.)2005,436,967-972.
[10] Wu, Q.; Qu, F.; Wan, J.; Zhu, X.; Xia, Y.; Peng, L. Design, synthesis, and characterization ofphotolabeling probes for the study of the mechanisms of the antiviral effects of ribavirin, Helv. Chim.Acta2004,87,811-819.
[11] Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Synthesis of5-aryltriazoleribonucleosides via suzuki coupling and promoted by microwave irradiation, Tetrahedron Lett.2006,47,6727-6731.
[12] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[13] Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L. Arylethynyltriazole acyclonucleosidesinhibit hepatitis c virus replication, Bioorg. Med. Chem. Lett.2008,18,3321-3327.
[14] Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Discovery of novel arylethynyltriazole ribonucleosides with selective and effective antiviral andantiproliferative activity, J. Med. Chem.2009,52,1144-1155.
[15] Xia, Y.; Liu, Y.; Wan, J.; Wang, M.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. Novel triazoleribonucleoside down-regulates heat shock protein27and induces potent anticancer activity ondrug-resistant pancreatic cancer, J. Med. Chem.2009,52,6083-6096.
[16] Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.; Peng, L. Synthesis of bitriazolylnucleosides and unexpectedly different reactivity of azidotriazole nucleoside isomers in the huisgenreaction, Org. Biomol. Chem.2007,5,1695-1701.
[17] Li, W.; Xia, Y.; Fan, Z.; Qu, F.; Wu, Q.; Peng, L. Bitriazolyl acyclonucleosides with antiviralactivity against tobacco mosaic virus, Tetrahedron Lett.2008,49,2804-2809.
[18] Xia, Y.; Wang, M.; Demaria, O.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna Juan, L.; Alexopoulou, L.;Peng, L. A novel bitriazolyl acyclonucleoside endowed with dual antiproliferation andimmunomodulatory activity, J. Med. Chem.2012, DOI:10.1021/jm300534u.
[19] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective n-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[20] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[21] Liu, Y.; Xia, Y.; Li, W.; Cong, M.; Maggiani, A.; Leyssen, P.; Qu, F.; Neyts, J.; Peng, L.S-aryltriazole acyclonucleosides: Synthesis and biological evaluation against hepatitis c virus, Bioorg.Med. Chem. Lett.2010,20,3610-3613.
[22] Xia, Y.; Liu, Y.; Rocchi, P.; Wang, M.; Fan, Y.; Qu, F.; Iovanna, J. L.; Peng, L. Targeting heatshock factor1with a triazole nucleoside analog to elicit potent anticancer activity on drug-resistantpancreatic cancer, Cancer Lett.2012,318,145-153.
[23] Peng, L.; Rocchi, P.; Iovanna, J.; Xia, Y.; Qu, F.; Wan, J.; Liu, Y.; Wang, M.; Novel triazolenucleoside derivatives, their preparation and their application in therapeutics. PCT/EP2009/055213.WO/2009/133147. Neyts, J.; Peng, L.; Qu, F.; Zhu, R.; Novel viral replication inhibitors,PCT/BE2008/000059. WO/2009/015446.
[24] Perreux, L.; Loupy, A. A tentative rationalization of microwave effects in organic synthesisaccording to the reaction medium, and mechanistic considerations, Tetrahedron2001,57,9199-9223.
[25] Kappe, C. O. Synthetic methods. Controlled microwave heating in modern organic synthesis,Angew. Chem. Int. Ed.2004,43,6250-6284.
[26] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination,Angew. Chem., Int. Ed.2008,47,6338-6361.
[27] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenuesfor modifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[28] Champeil, E.; Pradhan, P.; Lakshman, M. K. Palladium-catalyzed synthesis of nucleosideadducts from bay-and fjord-region diol epoxides, J. Org. Chem.2007,72,5035-5045.
[29] Fischer, C.; Koenig, B. Palladium-and copper-mediated n-aryl bond formation reactions for thesynthesis of biological active compounds, Beilstein J. Org. Chem.2011,7,59-74, No10.
[30] Reetz, M. T. Combinatorial transition-metal catalysis: Mixing monodentate ligands to controlenantio-, diastero-, and regioselectivity, Angew. Chem. Int. Ed.2008,47,2556-2588.
[31] Bedford, R. B.; Cazin, C. S. J.; Hazelwood, S. L. Simple mixedtricyclohexylphosphane-triarylphosphite complexes as extremely high-activity catalysts for the Suzukicoupling of aryl chlorides, Angew. Chem. Int. Ed.2002,41,4120-4122.
[32] Fors, B. P.; Buchwald, S. L. A multiligand based Pd catalyst for C-N cross-coupling reactions, J.Am. Chem. Soc.2010,132,15914-15917.
[33] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Corcoran, P.; Rosen, B. M.; Percec, V.Neopentylglycolborylation of aryl chlorides catalyzed by the mixed ligand system NiCl2(dppp)/dppf,Org. Lett.2009,11,4974-4977.
[34] Moldoveanu, C.; Wilson, D. A.; Wilson, C. J.; Leowanawat, P.; Resmerita, A.-M.; Liu, C.; Rosen,B. M.; Percec, V. Neopentylglycolborylation of ortho-substituted aryl halides catalyzed by NiCl2-basedmixed-ligand systems, J. Org. Chem.2010,75,5438-5452.
[35] Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. NiCl2(dppe)-catalyzed cross-coupling ofaryl mesylates, arenesulfonates, and halides with arylboronic acids, J. Org. Chem.2004,69,3447-3452.
[1] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective N-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[2] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[3]李蔚，武汉大学博士论文，"1,2,4-三氮唑开环核苷型抗病毒药物先导物的设计、合成、表征及筛选"，2009.
[4] Kappe, C. O. Synthetic methods. Controlled microwave heating in modern organic synthesis,Angew. Chem. Int. Ed.2004,43,6250-6284.
[5] Kappe, C. O.; Dallinger, D. The impact of microwave synthesis on drug discovery, Nat. Rev. DrugDiscovery2006,5,51-63.
[6] Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Synthesis of5-aryltriazoleribonucleosides via Suzuki coupling and promoted by microwave irradiation, Tetrahedron Lett.2006,47,6727-6731.
[7] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[8] Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L. Arylethynyltriazole acyclonucleosidesinhibit hepatitis c virus replication, Bioorg. Med. Chem. Lett.2008,18,3321-3327.
[9] Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Discovery of novel arylethynyltriazole ribonucleosides with selective and effective antiviral andantiproliferative activity, J. Med. Chem.2009,52,1144-1155.
[10] Chen, S.; Huang, H.; Liu, X.; Shen, J.; Jiang, H.; Liu, H. Microwave-assisted efficientcopper-promoted N-arylation of amines with arylboronic acids, J. Comb. Chem.2008,10,358-360.
[1] Li, W.; Fan, Y.; Xia, Y.; Rocchi, P.; Zhu, R.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Cu-mediated selective N-arylation of aminotriazole acyclonucleosides, Helv. Chim. Acta2009,92,1503-1513.
[2] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[3] Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification ofaryl halides, Acc. Chem. Res.2008,41,1534-1544.
[4] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination, Angew.Chem., Int. Ed.2008,47,6338-6361.
[5] Khalafi-Nezhad, A.; Zare, A.; Parhami, A.; Rad, M. N. S.; Nejabat, G. R. RegioselectiveN-arylation of some pyrimidine and purine nucleobases, Synth. Commun.2006,36,3549-3562.
[6] Fischer, C.; Koenig, B. Palladium-and copper-mediated N-aryl bond formation reactions for thesynthesis of biological active compounds, Beilstein J. Org. Chem.2011,7,59-74, No10.
[7] Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. Palladium-catalyzed C-N bondformation: Facile and general synthesis of N6-aryl2'-deoxyadenosine analogues, J. Am. Chem. Soc.1999,121,6090-6091.
[8] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenues formodifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[9] Thomson, P. F.; Lagisetty, P.; Balzarini, J.; De Clercq, E.; Lakshman, M. K. Palladium-catalyzedaryl amination reactions of6-bromo-and6-chloropurine nucleosides, Adv. Synth. Catal.2010,352,1728-1735.
[10] Pratap, R.; Parrish, D.; Gunda, P.; Venkataraman, D.; Lakshman, M. K. Influence of biarylphosphine structure on C-N and C-C bond formation, J. Am. Chem. Soc.2009,131,12240-12249.
[11] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[12] Wan, J.; Zhu, R.; Xia, Y.; Qu, F.; Wu, Q.; Yang, G.; Neyts, J.; Peng, L. Synthesis of5-aryltriazoleribonucleosides via suzuki coupling and promoted by microwave irradiation, Tetrahedron Lett.2006,47,6727-6731.
[13] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[14] Zhu, R.; Wang, M.; Xia, Y.; Qu, F.; Neyts, J.; Peng, L. Arylethynyltriazole acyclonucleosidesinhibit hepatitis C virus replication, Bioorg. Med. Chem. Lett.2008,18,3321-3327.
[15] Wan, J.; Xia, Y.; Liu, Y.; Wang, M.; Rocchi, P.; Yao, J.; Qu, F.; Neyts, J.; Iovanna, J. L.; Peng, L.Discovery of novel arylethynyltriazole ribonucleosides with selective and effective antiviral andantiproliferative activity, J. Med. Chem.2009,52,1144-1155.
[16]朱瑞芝，武汉大学博士论文，"新型1,2,4-三氮唑开环核苷衍生物的设计、合成及表征"，2007.
[17] Chakraborti, D.; Colis, L.; Schneider, R.; Basu, A. K. Synthesis of n22'-deoxyguanosine adductsformed by1-nitropyrene, Org. Lett.2003,5,2861-2864.
[18] Xia, Y.; Li, W.; Qu, F.; Fan, Z.; Liu, X.; Berro, C.; Rauzy, E.; Peng, L. Synthesis of bitriazolylnucleosides and unexpectedly different reactivity of azidotriazole nucleoside isomers in the huisgenreaction, Org. Biomol. Chem.2007,5,1695-1701.
[19] Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Bite angle effects of diphosphines in c-cand c-x bond forming cross coupling reactions, Chem. Soc. Rev.2009,38,1099-1118.
[20] Fujita, K.-i.; Yamashita, M.; Puschmann, F.; Martinez Alvarez-Falcon, M.; Incarvito, C. D.;Hartwig, J. F. Organometallic chemistry of amidate complexes. Accelerating effect of bidentate ligandson the reductive elimination of N-aryl amidates from palladium(ii), J. Am. Chem. Soc.2006,128,9044-9045.
[21] Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Reek, J. N. H. Wide bite angle diphosphines:Xantphos ligands in transition metal complexes and catalysis, Acc. Chem. Res.2001,34,895-904.
[22] Jeulin, S.; De Paule, S. D.; Ratovelomanana-Vidal, V.; Genet, J.-P.; Champion, N.; Dellis, P.Chiral biphenyl diphosphines for asymmetric catalysis: Stereoelectronic design and industrialperspectives, Proc. Natl. Acad. Sci.2004,101,5799-5804.
[23] van Zeist, W.-J.; Visser, R.; Bickelhaupt, F. M. The steric nature of the bite angle, Chem.--Eur. J.2009,15,6112-6115.
[24] Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L. Ligand-mediated highlyeffective and selective C-N coupling for synthesizing bioactive N-aryltriazole acyclonucleosides, Org.Lett.2010,12,5712-5715.
[1] Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L. Ligand-mediated highlyeffective and selective C-N coupling for synthesizing bioactive n-aryltriazole acyclonucleosides, Org.Lett.2010,12,5712-5715.
[2] Liu, Y.; Xia, Y.; Fan, Y.; Maggiani, A.; Rocchi, P.; Qu, F.; Iovanna, J. L.; Peng, L. N-aryltriazoleribonucleosides with potent antiproliferative activity against drug-resistant pancreatic cancer, Bioorg.Med. Chem. Lett.2010,20,2503-2507.
[3] Xia, Y.; Qu, F.; Peng, L. Triazole nucleoside derivatives bearing aryl functionalities on thenucleobases show antiviral and anticancer activity, Mini-Rev. Med. Chem.2010,10,806-821.
[4] Fors, B. P.; Buchwald, S. L. A multiligand based Pd catalyst for C-N cross-coupling reactions, J.Am. Chem. Soc.2010,132,15914-15917.
[5] Zhu, R.; Qu, F.; Quelever, G.; Peng, L. Direct synthesis of5-aryltriazole acyclonucleosides viasuzuki coupling in aqueous solution, Tetrahedron Lett.2007,48,2389-2393.
[6] Lakshman, M. K.; Keeler, J. C.; Hilmer, J. H.; Martin, J. Q. Palladium-catalyzed C-N bondformation: Facile and general synthesis of N6-aryl2'-deoxyadenosine analogues, J. Am. Chem. Soc.1999,121,6090-6091.
[7] Lakshman, M. K. Palladium-catalyzed C-N and C-C cross-couplings as versatile, new avenues formodifications of purine2'-deoxynucleosides, J. Organomet. Chem.2002,653,234-251.
[8] Thomson, P. F.; Lagisetty, P.; Balzarini, J.; De Clercq, E.; Lakshman, M. K. Palladium-catalyzedaryl amination reactions of6-bromo-and6-chloropurine nucleosides, Adv. Synth. Catal.2010,352,1728-1735.
[9] Klingensmith, L. M.; Strieter, E. R.; Barder, T. E.; Buchwald, S. L. New insights intoXantphos/Pd-catalyzed C-N bond forming reactions: A structural and kinetic study, Organometallics2006,25,82-91.
[10] Amatore, C.; Jutand, A.; Thuilliez, A. Formation of palladium(0) complexes from Pd(OAc)2anda bidentate phosphine ligand (dppp) and their reactivity in oxidative addition, Organometallics2001,20,3241-3249.
[11] Surry, D. S.; Buchwald, S. L. Biaryl phosphane ligands in palladium-catalyzed amination, Angew.Chem., Int. Ed.2008,47,6338-6361.
[12] Fan, Y.; Xia, Y.; Tang, J.; Ziarelli, F.; Qu, F.; Rocchi, P.; Iovanna, J. L.; Peng, L. An efficientmixed-ligand Pd catalytic system to promote C-N coupling for the synthesis of N-arylaminotriazolenucleosides, Chem.--Eur. J.2012,18,2221-2225.
[1] Sidwell, R. W.; Huffman, J. H.; Khare, G. P.; Allen, L. B.; Witkowski, J. T.; Robins, R. K.Broad-spectrum antiviral activity of virazole.1-beta-d-ribofuranosyl-1,2,4-triazole-3-carboxamide,Science1972,177,705-706.
[2] Li, D.; Xie, K.; Wolff, R.; Abbruzzese, J. L. Pancreatic cancer, Lancet2004,363,1049-1057.
[3] Pierantoni, C.; Pagliacci, A.; Scartozzi, M.; Berardi, R.; Bianconi, M.; Cascinu, S. Pancreaticcancer: Progress in cancer therapy, Crit Rev Oncol Hematol2008,67,27-38.
[4] Rivera, F.; Lopez-Tarruella, S.; Vega-Villegas, M. E.; Salcedo, M. Treatment of advancedpancreatic cancer: From gemcitabine single agent to combinations and targeted therapy, Cancer Treat.Rev.2009,35,335-339.
[5] Berlin, J.; Benson, A. B., III Gemcitabine remains the standard of care for pancreatic cancer, Nat.Rev. Clin. Oncol.2010,7,135-137.
[6] Mukherji, D.; Pezaro, C. J.; De-Bono, J. S. For the treatment of prostate cancer, Expert Opin.Invest. Drugs2012,21,227-233.
[7]王孟华，武汉大学博士论文，"新型1,2,4-三氮唑核苷的合成及其生物活性研究"，2009
[8] Xia, Y.; Liu, Y.; Rocchi, P.; Wang, M.; Fan, Y.; Qu, F.; Iovanna, J. L.; Peng, L. Targeting heatshock factor1with a triazole nucleoside analog to elicit potent anticancer activity on drug-resistantpancreatic cancer, Cancer Lett.2012,318,145-153.
[9] Fan, Y.; Xia, Y.; Tang, J.; Ziarelli, F.; Qu, F.; Rocchi, P.; Iovanna, J. L.; Peng, L. An efficientmixed-ligand Pd catalytic system to promote C-N coupling for the synthesis of N-arylaminotriazolenucleosides, Chem.--Eur. J.2012,18,2221-2225.
[10] Fan, Y.; Xia, Y.; Tang, J.; Rocchi, P.; Qu, F.; Iovanna, J.; Peng, L. Ligand-mediated highlyeffective and selective C-N coupling for synthesizing bioactive N-aryltriazole acyclonucleosides, Org.Lett.2010,12,5712-5715.