一些嘧啶并环类化合物在药物开发中的应用研究
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摘要
先导化合物的发现是药物发现阶段的关键步骤，是目前药物化学研究中最活跃的一个领域。基于优势结构单元构建小分子库的理念吸引了药物化学家越来越多的注意，并已成为药物化学的研究热点之一。本论文工作主要围绕一些嘧啶并环类化合物的合成方法学研究和多样性导向的化合物库设计与合成及其相关生物活性的评价来展开。第一部分：含有嘧啶并环结构单元的活性化合物数目众多，许多已上市及临床阶段的药物分子中都含该结构单元，是优势结构之一。我们在合成广谱抗真菌药物伏立康唑中间体6-乙基-5-氟-4-羟基嘧啶过程中，发现Pd-C/H_2/NaHCO_3体系能有效脱除嘧啶环上的氯原子。深入研究发现该体系能区域选择性地优先氢解诸多2，4-二氯嘧啶类化合物中的4-位氯原子，得到2-氯嘧啶类产物。初步的方法学研究表明Pd-C/H_2/NaHCO_3条件下区域选择性氢解2，4-二氯嘧啶类化合物是现有的2-氯嘧啶类化合物制备方法的有效补充。在上述方法学研究的基础上，我们设计并合成了三个具有2-3个不同反应活性位点的嘧啶并环砌块A1-3，作为构建该类小分子库的起始原料。通过亲核取代反应和Suzuki偶联反应，砌块A1依次与芳胺砌块B1-5、仲胺砌块C1-6和硼酸砌块D1-10作用，基于尽可能拓展化学空间的多样性导向原则，我们初步构建了一个含80个化合物的嘧啶并环类小分子库Library 1，并在蛋白激酶c-Met上对化合物的抑制活性进行了评价。结果表明Library 1中的绝大部分化合物不是很好的c-Met抑制剂，其中LXY-78是活性最好的化合物，在浓度为10μg/mL时，对c-Met的抑制率为47．8%。Library 1在腺苷受体上的评价工作仍在进行之中。第二部分：S-腺苷同型半胱氨酸水解酶(SAHH)是一种在细胞内广泛存在的酶，它催化腺苷同型半胱氨酸(AdoHcy)水解生成腺苷(Ado)和同型半胱氨酸(Hcy)。抑制SAHH将导致细胞内AdoHcy的蓄积，从而对转甲基反应产生反馈性抑制作用。与机体其它细胞相比，淋巴细胞的活化更依赖于这种由SAHH调控的甲基化作用，因而抑制SAHH的活性，就有可能实现免疫抑制。与早期的SAHH不可逆抑制剂相比，DZ2002是近年来研究比较多的一种Ⅲ型可逆抑制剂。研究发现DZ2002在有效降低不可逆抑制剂所固有的细胞毒性的同时，仍然保持了良好的酶抑制活性。DZ2002在一系列炎症和自身免疫性疾病的动物模型上都具有良好的预防和治疗作用。DZ2002具有较高的治疗指数，在毒性剂量和治疗剂量间有较宽的距离，这些都提示DZ2002有可能发展成为高效低毒的新型免疫抑制剂。基于DZ2002的良好的应用前景，有必要对它的合成工艺进行研究。我们以价廉易得的大宗化商品L-苹果酸为手性原料，丙酮叉保护，硼烷选择性还原4-位羧基到醇。所得醇转化为对甲苯磺酸酯后，与商品化原料腺嘌呤偶联，所得偶联产物于甲醇中用乙酰氯处理，在脱去丙酮叉保护的同时实现甲酯化反应，得到目标分子DZ2002。以L-苹果酸计，经5步反应，重结晶后总收率为6．54%，所得样品经测试满足临床前研究的各项质量指标。基于上述合成路线，我们首次报道了DZ2002的比旋光值和ee值，为今后进一步的工艺优化奠定了基础。DZ2002小试工艺合成路线简洁，所用原料成本低，反应条件温和，后处理方便，易于放大。为了进一步考察手性与DZ2002生物活性的关系，我们设计并合成了DZ2002的三个相关异构体。活性测试结果显示，四个化合物中DZ2002的酶抑制活性最强(IC_(50)=21．2．μM，Table 3-1)，SAHH抑制活性顺序依次为：(S)-DZ2002＞(Rac)-DZ2002＞(R)-DZ2002＞(Ketone)-DZ2002。四个化合物的体外免疫抑制活性与它们对SAHH的抑制活性相一致，DZ2002的体外免疫抑制活性最强。这些结果表明DZ2002分子中的手性中心采取(S)绝对构型最有利于活性的保持。通过计算模拟DZ2002与SAHH的结合情况，发现DZ2002中手性的不同会导致化合物与酶结合时其边链的空间伸展方向的不同，并导致与SAHH残基形成氢键个数的不同，这在一定程度上解释了DZ2002分子中的手性影响其活性的作用机制。
With a DOS (diversity-oriented synthesis) approach,the installation of suitablefunctionalities at suitable places of certain privileged structure may lead to a higherscreening hit rate later.This strategy of building libraries of small molecules basedon some privileged structures has attracted many medicinal chemists,representingone trend in lead discovery in recent years.
1)Many bio-active compounds contain pyrimidine-fused cyclic structures,which also occur in many drugs on market or under clinical stage.During oursynthesis of 6-ethyl-7-fluoro-4-hydroxy uracil,the key intermediate of Voriconazole,we found Pd-C/H_2/NaHCO_3 system can replace the chlorine atom in the pyrimidinering with a hydrogen atom efficiently.Further application study showed that many2-chloropyrimidines can be obtained regioselectively from readily available2,4-dichloropyrimidines using above system in good to excellent yields,constitutingan useful alternative synthesis of 2-chloropyrimidines.
Based on above synthetic methodology study,we designed and prepared threepyrimidine building blocks A1-3 with 2-3 different reacting points.Employingsubstitution and Suzuki coupling reaction,aryl amine blocks B1-5,secondary amineblocks C1-6 and boric acid blocks D1-10 were installed to block A1 smoothly,leading to the construction of Library 1 containing 80 compounds.Library 1 wasevaluated on protein kinase c-Met and Adenosine Receptors.LXY-78,the mostpotent compound on c-Met in Library 1,displayed a 47.8% enzyme inhibition inconcentration of 10 mg/mL.Evaluations on Adenosine Receptors are currently underprogress.
2)Within recent years,4-(6-Amino-purin-9-yl)-2(S)-hydroxy-butyric acidmethyl ester (DZ2002) has been recognized as a potent typeⅢreversible inhibitor ofSAHH.DZ2002 is able to reversibly bind to the open form of the enzyme, maintaining a similar potency with much reduced toxicity which hampers furtherclinical applications of irreversible SAHH inhibitors.Biological study indicatesDZ2002 is a promising noval therapeutic agent for immune-related diseases.
Due to its promising prospect,there is a need to develop a practical syntheticprocess to meet the sample need for related pre-clinical study.Our synthesis startedwith cheap and commercially available optical malic acid.In brief,(S)-malic acid wasfirst transformed to acetonide.Acetonide was reduced to alcohol,which wasimmediately converted to its tosylate.Coupling of tosylate with adenine gave desiredkey intermediate in a yield of 32% after silica-gel chromatograph.The keyintermediate was readily transformed to DZ2002 upon spontaneous deprotection andesterification in methanol solution of HCl.Because of the rigid conformation ofacetonide during reaction sequences,2-chiral center was highly reserved and potentialracemization was avoided.Following this process,target DZ202 was obtained in atotal yield of 6.54% after 5 steps reaction and recrystallization.According to thisprocess,about 120 grams of DZ2002 was synthesized and used for related biologicalstudy.
We also designed and synthesized DZ2002 related steroisomers so as toinvestigate the necessaty of chiral center.Later biological study showed that that(S)-DZ2002 was the strongest inhibitor among four compounds (IC_(50)=21.2μM).The order of enzyme inhibition potency was (S)-Z2002＞(Rac)-DZ2002＞(R)-DZ2002＞(Ketone)-DZ2002.Respective suppressive potency appeared to matchthe inhibitory potency of the SAHH.These results indicated that maintenance of2-chiral center in the molecule as (S)-configuration is important for binding withSAHH.Simplified docking results showed that different numbers of hydrogen bondsinteracted with SAHH was formed providing useful information to understand theirefficacy difference.
With a DOS (diversity-oriented synthesis) approach,the installation of suitablefunctionalities at suitable places of certain privileged structure may lead to a higherscreening hit rate later.This strategy of building libraries of small molecules basedon some privileged structures has attracted many medicinal chemists,representingone trend in lead discovery in recent years.
1)Many bio-active compounds contain pyrimidine-fused cyclic structures,which also occur in many drugs on market or under clinical stage.During oursynthesis of 6-ethyl-7-fluoro-4-hydroxy uracil,the key intermediate of Voriconazole,we found Pd-C/H_2/NaHCO_3 system can replace the chlorine atom in the pyrimidinering with a hydrogen atom efficiently.Further application study showed that many2-chloropyrimidines can be obtained regioselectively from readily available2,4-dichloropyrimidines using above system in good to excellent yields,constitutingan useful alternative synthesis of 2-chloropyrimidines.
Based on above synthetic methodology study,we designed and prepared threepyrimidine building blocks A1-3 with 2-3 different reacting points.Employingsubstitution and Suzuki coupling reaction,aryl amine blocks B1-5,secondary amineblocks C1-6 and boric acid blocks D1-10 were installed to block A1 smoothly,leading to the construction of Library 1 containing 80 compounds.Library 1 wasevaluated on protein kinase c-Met and Adenosine Receptors.LXY-78,the mostpotent compound on c-Met in Library 1,displayed a 47.8% enzyme inhibition inconcentration of 10 mg/mL.Evaluations on Adenosine Receptors are currently underprogress.
2)Within recent years,4-(6-Amino-purin-9-yl)-2(S)-hydroxy-butyric acidmethyl ester (DZ2002) has been recognized as a potent typeⅢreversible inhibitor ofSAHH.DZ2002 is able to reversibly bind to the open form of the enzyme, maintaining a similar potency with much reduced toxicity which hampers furtherclinical applications of irreversible SAHH inhibitors.Biological study indicatesDZ2002 is a promising noval therapeutic agent for immune-related diseases.
Due to its promising prospect,there is a need to develop a practical syntheticprocess to meet the sample need for related pre-clinical study.Our synthesis startedwith cheap and commercially available optical malic acid.In brief,(S)-malic acid wasfirst transformed to acetonide.Acetonide was reduced to alcohol,which wasimmediately converted to its tosylate.Coupling of tosylate with adenine gave desiredkey intermediate in a yield of 32% after silica-gel chromatograph.The keyintermediate was readily transformed to DZ2002 upon spontaneous deprotection andesterification in methanol solution of HCl.Because of the rigid conformation ofacetonide during reaction sequences,2-chiral center was highly reserved and potentialracemization was avoided.Following this process,target DZ202 was obtained in atotal yield of 6.54% after 5 steps reaction and recrystallization.According to thisprocess,about 120 grams of DZ2002 was synthesized and used for related biologicalstudy.
We also designed and synthesized DZ2002 related steroisomers so as toinvestigate the necessaty of chiral center.Later biological study showed that that(S)-DZ2002 was the strongest inhibitor among four compounds (IC_(50)=21.2μM).The order of enzyme inhibition potency was (S)-Z2002＞(Rac)-DZ2002＞(R)-DZ2002＞(Ketone)-DZ2002.Respective suppressive potency appeared to matchthe inhibitory potency of the SAHH.These results indicated that maintenance of2-chiral center in the molecule as (S)-configuration is important for binding withSAHH.Simplified docking results showed that different numbers of hydrogen bondsinteracted with SAHH was formed providing useful information to understand theirefficacy difference.
引文
1． 黄河花；江骥；胡蓓，加速药物研发新方式-微剂量给药研究．中国新药杂志2009，18，(1)，12-16．
2． 邹栩；顾凯，世界新药研发动向．中国新药杂志2007，16，(22)，1821-1826．
3. Severinsen,R.;Bourne,G.T.;Tran,T.T.;Ankersen,M.;Begtrup,M.;Smythe,M.L.,Library of biphenyl privileged substructures using a safety-catch linker approach.Journal of Combinatorial Chemistry 2008,10,(4),557-566.
4. Rouhi,A.M.,Rediscovering natural products.Chemical & Engineering News 2003,81,(41),77.
5. Newman,D.J.,Natural products as leads to potential drugs:An old process or the new hope for drug discovery? Journal of Medicinal Chemistry 2008,51,(9),2589-2599.
6. Henkel,T.;Brunne,R.M.;Muller,H.;Reichel,F.,Statistical investigation into the structural complementarity of natural products and synthetic compounds.Angewandte Chemie-International Edition 1999,38,(5),643-647.
7. Evans,B.E.;Rittle,K.E.;Bock,M.G.;Dipardo,R.M.;Freidinger,R.M.;Whitter,W.L.;Lundell,G.F.;Veber,D.F.;Anderson,P.S.;Chang,R.S.L.;Lotti,V.J.;Cerino,D.J.;Chen,T.B.;Kling,P.J.;Kunkel,K.A.;Springer,J.P.;Hirshfield,J.,Methods for Drug Discovery-Development of Potent,Selective,Orally Effective Cholecystokinin Antagonists.Journal of Medicinal Chemistry 1988,31,(12),2235-2246.
8. Andrews,P.R.;Lloyd,E.J.,Molecular-Conformation and Biological-Activity of Central Nervous-System Active-Drugs.Medicinal Research Reviews 1982,2,(4),355-393.
9. Liu,J.F.;Wilson,C.J.;Ye,P.;Sprague,K.;Sargent,K.;Si,Y.;Beletsky,G.;Yohannes,D.;Ng,S.C.,Privileged structure-based quinazolinone natural product-templated libraries:Identification of novel tubulin polymerization inhibitors.Bioorganic & Medicinal Chemistry Letters 2006,16,(3),686-690.
10.Rheault,T.R.;Caferro,T.R.;Dickerson,S.H.;Donaldso,K.H.;Gaul,M.D.;Goetz,A.S.;Mullin,R.J.;McDonald,O.B.;Petrov,K.G.;Rusnak,D.W.;Shewchuk,L.M.;Spehar,G.M.;Truesdale,A.T.;Vanderwall,D.E.;Wood,E.R.;Uehling,D.E.,Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors.Bioorganic & Medicinal Chemistry Letters 2009,19,(3),817-820.
11．邓世明；林强，新药研究思路与方法．人民卫生出版社：2008．
12．李钧，最新药品注册技术精讲(第二版)．化学工业出版社：2008．
13.Yuan,C.S.;Saso,Y.;Lazarides,E.;Borchardt,R.T.;Robins,M.J.,Recent advances in S-adenosyl-L-homocysteine hydrolase inhibitors and their potential clinical applications.Expert Opinion on Therapeutic Patents 1999,9,(9),1197-1206.
14．付云峰．可逆性S-腺苷同型半胱氨酸水解酶抑制剂(DZ2002)的免疫抑制活性及其作用机制的研究．中科院上海药物研究所，2006．
15．付任重．新型嘧啶并环分子的设计与合成．吉林大学，2008．
16.Kompis,I.M.;Islam,K.;Then,R.L.,DNA and RNA synthesis:Antifolates.Chemical Reviews 2005,105,(2),593-620.
17.Gangjee,A.;Shi,J.F.;Queener,S.F.,Synthesis and biological activities of conformationally restricted,tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases.Journal of Medicinal Chemistry 1997,40,(12),1930-1936.
18.McGuire,J.J.,Anticancer antifolates:Current status and furture directions.Current Pharmaceutical Design 2003,9,(31),2593-2613.
19.Ridley,R.G,Medical need,scientific opportunity and the drive for antimalarial drugs.Nature 2002,415,(6872),686-693.
20.Gangjee,A.;Qiu,Y.B.;Li,W.;Kisliuk,R.L.,Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: Classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine Antifolates.Journal of Medicinal Chemistry 2008,51,(18),5789-5797.
21.Gangjee,A.;Li,W.;Yang,J.;Kisliuk,R.L.,Design,synthesis,and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.Journal of Medicinal Chemistry 2008,51,(1),68-76.
22.Gangjee,A.;Jain,H.D.;Queener,S.F.;Kisliuk,R.L.,The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.Journal of Medicinal Chemistry 2008,51,(15),4589-4600.
23.Gangjee,A.;Zeng,Y.B.;Talreja,T.;McGuire,J.J.;Kisliuk,R.L.;Queener,S.F.,Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as antifolates.Journal of Medicinal Chemistry 2007,50,(13),3046-3053.
24.Gangjee,A.;Jain,H.D.;Phan,J.;Lin,X.;Song,X.H.;McGuire,J.J.;Kisliuk,R.L.,Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumor agents:Design,synthesis,and biological evaluation of classical and nonclassical pyrrolo[2,3-d]pyrimidine antifolates.Journal of Medicinal Chemistry 2006,49,(3),1055-1065.
25.Fredholm,B.B.;Chen,J.F.;Cunha,R.A.;Svenningsson,P.;Vaugeois,J.M.,Adenosine and brain function.International Review ofNeurobiology,Vol 63 2005,63,191-270.26.Fredholm,B.B.;Cunha,R.A.;Svenningsson,P.,Pharmacology of adenosine A(2A) receptors and therapeutic applications.Current Topics in Medicinal Chemistry 2003,3,(4),413-426.
27.Fredholm,B.B.;Ijzerman,A.P.;Jacobson,K.A.;Klotz,K.N.;Linden,J.,International Union of Pharmacology.XXV.Nomenclature and classification of adenosine receptors.Pharmacological Reviews 2001,53,(4),527-552.
28.Akkari,R.;Burbiel,J.C.;Hockemeyer,J.;Muller,C.E.,Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs.Current Topics in Medicinal Chemistry 2006,6,(13),1375-1399.
29.Joshi,B.V.;Jacobson,K.A.,Purine derivatives as ligands for A(3) adenosine receptors.Current Topics in Medicinal Chemistry 2005,5,(13),1275-1295.
30.Press,N.J.;Keller,T.H.;Tranter,P.;Beer,D.;Jones,K.;Faessler,A.;Heng,R.H.;Lewis,C.;Howe,T.;Gedeck,P.;Mazzoni,L.;Fozard,J.R.,New highly potent and selective adenosine A(3) receptor antagonists.Current Topics in Medicinal Chemistry 2004,4,(8),863-870.
31.Cacciari,B.;Pastorin,G.;Spalluto,G.,Medicinal chemistry of A2A adenosine receptor antagonists.Current Topics in Medicinal Chemistry 2003,3,(4),403-411.
32.Cristalli,G.;Lambertucci,C.;Taffi,S.;Vittori,S.;Volpini,R.,Medicinal chemistry of adenosine A(2A) receptor agonists.Current Topics in Medicinal Chemistry 2003,3,(4),387-401.
33.Webb,R.L.;Sills,M.A.;Chovan,J.P.;Balwierczak,J.L.;Francis,J.E.,Cgs-21680-a Potent Selective Adenosine A2 Receptor Agonist.Cardiovascular Drug Reviews 1992,10,(1),26-53.
34.Francis,J.E.;Cash,W.D.;Barbaz,B.S.;Bernard,P.S.;Lovell,R.A.;Mazzenga,G.C.;Friedmann,R.C.;Hyun,J.L.;Braunwalder,A.F.;Loo,P.S.;Bennett,D.A.,Synthesis and Benzodiazepine Binding-Activity of a Series of Novel[1,2,4]Triazolo[1,5-C]Quinazolin-5(6h)-Ones.Journal of Medicinal Chemistry 1991,34,(1),281-290.
35.Francis,J.E.;Webb,R.L.;Ghai,G.R.;Hutchison,A.J.;Moskal,M.A.;Dejesus,R.;Yokoyama,R.;Rovinski,S.L.;Contardo,N.;Dotson,R.;Barclay,B.;Stone,G.A.;Jarvis,M.F.,Highly Selective Adenosine-A2 Receptor Agonists in a Series of N-Alkylated 2-Aminoadenosines.Journal of Medicinal Chemistry 1991,34,(8),2570-2579.
36.Francis,J.E.;Cash,W.D.;Psychoyos,S.;Ghai,G.;Wenk,P.;Friedmann,R.C.;Atkins,C.;Warren,V.;Furness,P.;Hyun,J.L.;Stone,G.A.;Desai,M.;Williams,M.,Structure Activity Profile of a Series of Novel Triazoloquinazoline Adenosine Antagonists.Journal of Medicinal Chemistry 1988,31,(5),1014-1020.
37.Ghai,G.;Francis,J.E.;Williams,M.;Dotson,R.A.;Hopkins,M.F.;Cote,D.T.;Goodman,F.R.;Zimmerman,M.B.,Pharmacological Characterization of Cgs-15943a-a Novel Nonxanthine Adenosine Antagonist.Journal of Pharmacology and Experimental Therapeutics 1987,242,(3),784-790.
38.Cosimelli,B.;Greco,G.;Ehlardo,M.;Novellino,E.;Da Settimo,F.;Taliani,S.;La Motta,C.;Bellandi,M.;Tuccinardi,T.;Martinelli,A.;Ciampi,O.;Trincavelli,M.L.;Martini,C.,Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel,potent,and selective A(3) adenosine receptor antagonists.Journal of Medicinal Chemistry 2008,51,(6),1764-1770.
39.Kalla,R.V.;Elzein,E.;Perry,T.;Li,X.F.;Palle,V.;Varkhedkar,V.;Gimbel,A.;Maa,T.;Zeng,D.W.;Zablocki,J.,Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines:High affinity and selective A(2B) adenosine receptor antagonists.Journal of Medicinal Chemistry 2006,49,(12),3682-3692.
40.Chang,L.C.W.;Spanjersberg,R.F.;Kunzel,J.;Brussee,J.;Ijzerman,A.P.,2,6-disubstituted and 2,6,8-trisubstituted purines as adenosine receptor antagonists.Journal of Medicinal Chemistry 2006,49,(10),2861-2867.
41.Lanier,M.C.;Moorjani,M.;Luo,Z.Y.;Chen,Y.S.;Lin,E.;Tellew,J.E.;Zhang,X.H.;Williams,J.P.;Gross,R.S.;Lechner,S.M.;Markison,S.;Joswig,T.;Kargo,W.;Piercey,J.;Santos,M.;Malany,S.;Zhao,M.;Petroski,R.;Crespo,M.I.;Diaz,J.L.;Saunders,J.;Wen,J.;O'Brien, Z.; Jalali, K.; Madan, A.; Slee, D. H.,N-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A(2A) Receptor Antagonists with Improved Drug Like Properties and in Vivo Efficacy.Journal of Medicinal Chemistry 2009,52,(3),709-717.
42.Slee,D.H.;Zhang,X.H.;Moorjani,M.;Lin,E.;Lanier,M.C.;Chen,Y.S.;Rueter,J.K.;Lechner,S.M.;Markison,S.;Malany,S.;Joswig,T.;Santos,M.;Gross,R.S.;Williams,J.P.;Castro-Palomino,J.C.;Crespo,M.I.;Prat,M.;Gual,S.;Diaz,J.L.;Wen,J.;O'Brien,Z.;Saunders,J.,Identification of novel,water-soluble,2-amino-N-pyrimidin-4-yl acetamides as A(2A) receptor antagonists with in vivo efficacy.Journal of Medicinal Chemistry 2008,51,(3),400-406.
43.Slee,D.H.;Chen,Y.;Zhang,X.H.;Moorjani,M.;Lanier,M.C.;Lin,E.;Rueter,J.K.;Williams,J.P.;Lechner,S.M.;Markison,S.;Malany,S.;Santos,M.;Gross,R.S.;Jalali,K.;Sai,Y.;Zuo,Z.Y.;Yang,C.;Castro-Palomino,J.C.;Crespo,M.I.;Prat,M.;Gual,S.;Diaz,J.L.;Saunders, J., 2-amino-N-pyrimidin-4-ylacetamides as A(2A) receptor antagonists: 1.Structure-activity relationships and optimization of heterocyclic substituents.Journal of Medicinal Chemistry 2008,51,(6),1719-1729.
44.Zhang,X.H.;Tellew,J.E.;Luo,Z.Y.;Moorjani,M.;Lin,E.;Lanier,M.C.;Chen,Y.;Williams,J.P.;Saunders,J.;Lechner,S.M.;Markison,S.;Joswig,T.;Petroski,R.;Piercey,J.;Kargo,W.;Malany,S.;Santos,M.;Gross,R.S.;Wen,J.;Jalali,K.;O'Brien,Z.;Stotz,C.E.; Crespo, M. I.; Diaz, J. L.; Slee, D. H., Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-l-yl)-6-pyridylpyrimidines as A(2A) Adenosine Receptor Antagonists for the Treatment of Parkinson's Disease.Journal of Medicinal Chemistry 2008,51,(22),7099-7110.
45.Morizzo,E.;Capelli,F.;Lenzi,O.;Catarzi,D.;Varano,F.;Filacchioni,G.;Vincenzi,F.;Varani,K.;Borea,P.A.;Colotta,V.;Moro,S.,Scouting human A(3) adenosine receptor antagonist binding mode using a molecular simplification approach:From triazoloquinoxaline to a pyrimidine skeleton as a key study.Journal of Medicinal Chemistry 2007,50,(26),6596-6606.
46.Gillespie,R.J.;Bamford,S.J.;Botting,R.;Comer,M.;Denny,S.;Gaur,S.;Griffin,M.;Jordan,A.M.;Knight,A.R.;Lerpiniere,J.;Leonardi,S.;Lightowler,S.;McAteer,S.;Merrett,A.;Misra,A.;Padfield,A.;Reece,M.;Saadi,M.;Selwood,D.L.;Stratton,G.C.;Surry,D.;Todd,R.;Tong,X.;Ruston,V.;Upton,R.;Weiss,S.M.,Antagonists of the Human A(2A)Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines.Journal of Medicinal Chemistry 2009,52,(1),33-47.
47.Neustadt,B.R.;Liu,H.;Hao,J.S.;Greenlee,W.J.;Stamford,A.W.;Foster,C.;Arik,L.;Lachowicz,J.;Zhang,H.T.;Bertorelli,R.;Fredduzzi,S.;Varty,G.;Cohen-Williams,M.;Ng,K.,Potent and selective adenosine A(2A) receptor antagonists:1,2,4-Triazolo[1,5-c]pyrimidines.Bioorganic & Medicinal Chemistry Letters 2009,19,(3),967-971.
48.Sharma,P.S.;Sharma,R.;Tyagi,T.,Receptor Tryosine Kinase Inhibitors as Potent Weapons in War Against Cancers.Current Pharmaceutical Design 2009,15,(7),758-776.
49.Akritopoulou-Zanze,I.;Hajduk,P.J.,Kinase-targeted libraries:The design and synthesis of novel,potent,and selective kinase inhibitors.Drug Discovery Today 2009,14,(5-6),291-297.
50.Gilfillan,A.M.;Rivera,J.,The tyrosine kinase network regulating mast cell activation.Immunological Reviews 2009,228,149-169.
51.Grant,S.,Therapeutic Protein Kinase Inhibitors.Cellular and Molecular Life Sciences 2009,66,(7),1163-1177.
52.Bridges,A.J.,Chemical inhibitors of protein kinases.Chemical Reviews 2001,101,(8),2541-2571.
53.Showalter,H.D.H.;Bridges,A.J.;Zhou,H.R.;Sercel,A.D.;McMichael,A.;Fry,D.W.,Tyrosine kinase inhibitors. 16. 6,5,6-tricyclic benzothieno[3,2-d]pyrimidines and pyrimido[5,4-b]-and-[4,5-b]indoles as potent inhibitors of the epidermal growth factor receptor tyrosine kinase.Journal of Medicinal Chemistry 1999,42,(26),5464-5474.
54.Kiselyov,A.S.;Smith,L.,Novel one pot synthesis of polysubstituted pyrazolo[1,5-a]-and imidazo[1,2-a]pyrimidines.Tetrahedron Letters 2006,47,(15),2611-2614.
55.Smith,L.;Piatnitski,E.L.;Kiselyov,A.S.;Ouyang,X.;Chen,X.L.;Burdzovic-Wizemann, S.;Xu,Y.J.;Wang,Y.;Rosler,R.L.;Patel,S.N.;Chiang,H.H.;Millign,D.L.;Columbus,J.;Wong, W. C.; Doody, J. F.; Hadari, Y. R., Tricyclic azepine derivatives:Pyrimido[4,5-b]-l,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors.Bioorganic & Medicinal Chemistry Letters 2006,16,(6),1643-1646.
56.Smith,L.;Wong,W.C.;Kiselyov,A.S.;Burdzovic-Wizemann,S.;Mao,Y.Y.;Xu,Y.J.;Duncton,M.A.J.;Kim,K.;Piatnitski,E.L.;Doody,J.F.;Wang,Y.;Rosler,R.L.;Milligan,D.;Columbus,J.;Balagtas,C.;Lee,S.P.Konovalov,A.;Hadari,Y.R.,Novel tricyclic azepine derivatives:Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines,thiazepines,and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase.Bioorganic & Medicinal Chemistry Letters 2006,16,(19),5102-5106.
57.Smaill,J.B.;Rewcastle,G.W.;Loo,J.A.;Greis,K.D.;Chan,O.H.;Reyner,E.L.;Lipka,E.;Showalter,H.D.H.;Vincent,P.W.;Elliott,W.L.;Denny,W.A.,Tyrosine kinase inhibitors.17.Irreversible inhibitors of the epidermal growth factor receptor:4-(phenylamino)quinazoline-and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions.Journal of Medicinal Chemistry 2000,43,(7),1380-1397.
58.Smaill,J.B.;Rewcastle,G.W.;Bridges,A.J.;Zhou,H.R.;Showalter,H.D.H.;Fry,D.W.;Nelson,J.M.;Sherwood,V.;Elliott,W.L.;Vincent,P.W.;DeJohn,D.E.;Loo,J.A.;Greis,K.D.;Chan,O.H.;Reyner,E.L.;Lipka,E.;Denny,W.A.,Tyrosine kinase inhibitors.17.Irreversible inhibitors of the epidermal growth factor receptor:4-(phenylamino)quinazoline-and 4-(phenylamino)pyrido[3,2-d]-pyrimidine-6-acrylamides bearing additional solubilizing functions (vol 43,pg 1380,2000).Journal of Medicinal Chemistry 2000,43,(16),3199-3199.
59.Rewcastle,G.W.;Murray,D.K.;Elliott,W.L.;Fry,D.W.;Howard,C.T.;Nelson,J.M.;Roberts,B.J.;Vincent,P.W.;Showalter,H.D.H.;Winters,R.T.;Denny,W.A.,Tyrosine kinase inhibitors.14.Structure-activity relationships for methylamino-substituted derivatives of 4-[(3-bromophenyl)amino]-6-(methylamino)pyrido[3,4-d]pyrimidine (PD 158780),a potent and specific inhibitor of the tyrosine kinase activity of receptors for the EGF family of growth factors.Journal of Medicinal Chemistry 1998,41,(5),742-751.
60.Rewcastle,G.W.;Bridges,A.J.;Fry,D.W.;Rubin,J.R.;Denny,W.A.,Tyrosine kinase inhibitors .12. Synthesis and structure-activity relationships for 6-substituted 4-(phenylamino)pyrimido[5,4-d]pyrimidines designed as inhibitors of the epidermal growth factor receptor.Journal of Medicinal Chemistry 1997,40,(12),1820-1826.
61.Rewcastle,G.W.;Palmer,B.D.;Thompson,A.M.;Bridges,A.J.;Cody,D.R.;Zhou,H.R.;Fry,D.W.;McMichael,A.;Denny,W.A.,Tyrosine kinase inhibitors.10.Isomeric 4-[(3-bromophenyl)amino]pyrido[d]-pyrimidines are potent ATP-binding site inhibitors of the tyrosine kinase function of the epidermal growth factor receptor.Journal of Medicinal Chemistry 1996,39,(9),1823-1835.
62.Manetti,F.;Brullo,C.;Magnani,M.;Mosci,F.;Chelli,B.;Crespan,E.;Schenone,S.;Naldini,A.;Bruno,O.;Trincavelli,M.L.;Maga,G.;Carraro,F.;Martini,C.;Bondavalli,F.;Bottat,M.,Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines.Journal of Medicinal Chemistry 2008,51,(5),1252-1259.
63.Echalier,A.;Bettayeb,K.;Ferandin,Y.;Lozach,O.;Clement,M.;Valette,A.;Liger,F.;Marquet, B.; Morris, J. C.; Endicott, J. A.; Joseph, B.; Meijer, L., Meriolins (3-(pyrimidin-4-yl)-7-azaindoles):Synthesis,kinase inhibitory activity,cellular effects,and structure of a CDK2/cyclin A/meriolin complex.Journal of Medicinal Chemistry 2008,51,(4),737-751.
64.Bathini,Y.;Singh,I.;Harvey,P.J.;Keller,P.R.;Singh,R.;Micetich,R.G.;Fry,D.W.;Dobrusin,E.M.;Toogood,P.L.,2-Aminoquinazoline inhibitors of cyclin-dependent kinases.Bioorganic & Medicinal Chemistry Letters 2005,15,(17),3881-3885.
65.Toogood,P.L.;Harvey,P.J.;Repine,J.T.;Sheehan,D.J.;VanderWel,S.N.;Zhou,H.R.;Keller,P.R.;McNamara,D.J.;Sherry,D.;Zhu,T.;Brodfuehrer,J.;Choi,C.;Barvian,M.R.;Fry,D.W.,Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.Journal of Medicinal Chemistry 2005,48,(7),2388-2406.
66.VanderWel,S.N.;Harvey,P.J.;McNamara,D.J.;Repine,J.T.;Keller,P.R.;Quin,J.;Booth, R. J.; Elliott,W. L.; Dobrusin,E. M.; Fry, D. W.;Toogood, P. L.,Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4.Journal of Medicinal Chemistry 2005,48,(7),2371-2387.
67.Gaillard,P.;Jeanclaude-Etter,I.;Ardissone,V.;Arkinstall,S.;Cambet,Y.;Camps,M.;Chabert,C.;Church,D.;Cirillo,R.;Gretener,D.;Halazy,S.;Nichols,A.;Szyndralewiez,C.;Vitte,P.A.;Gotteland,J.P.,Design and synthesis of the first generation of novel potent,selective,and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase.Journal of Medicinal Chemistry 2005,48,(14),4596-4607.
68.Klutchko,S.R.;Zhou,H.R.;Winters,R.T.;Tran,T.P.;Bridges,A.J.;Althaus,I.W.;Amato,D.M.;Elliott,W.L.;Ellis,P.A.;Meade,M.A.;Roberts,B.J.;Fry,D.W.;Gonzales,A.J.;Harvey,P.J.;Nelson,J.M.;Sherwood,V.;Han,H.K.;Pace,G.;Smaill,J.B.;Denny,W.A.;Showalter,H.D.H.,Tyrosine kinase inhibitors.19.6-alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors.Journal of Medicinal Chemistry 2006,49,(4),1475-1485.
69.Sabat,M.;VanRens,J.C.;Brugel,T.A.;Maier,J.;Laufersweiler,M.J.;Golebiowski,A.;De,B.;Easwaran,V.;Hsieh,L.C.;Rosegen,J.;Berberich,S.;Suchanek,E.;Janusz,M.J.,The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lyrnphocyte specific kinase (Lck).Bioorganic & Medicinal Chemistry Letters 2006,16,(16),4257-42.61.
70.Bookser,B.C.;Matelich,M.C.;Ollis,K.;Ugarkar,B.G.,Adenosine kinase inhibitors.4.6,8-disubstituted purine nucleoside derivatives.Synthesis,conformation,and enzyme inhibition.Journal of Medicinal Chemistry 2005,48,(9),3389-3399.
71.Bookser,B.C.;Ugarkar,B.G.;Matelich,M.C.;Lemus,R.H.;Allan,M.;Tsuchiya,M.;Nakane,M.;Nagahisa,A.;Wiesner,J.B.;Erion,M.D.,Adenosine kinase inhibitors.6.Synthesis,water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides and related compounds.Journal of Medicinal Chemistry 2005,48,(24),7808-7820.
72.Boyer,S.H.;Ugarkar,B.G.;Solbach,J.;Kopcho,J.;Matelich,M.C.;Ollis,K.;Gomez-Galeno,J.E.;Mendonca,R.;Tsuchiya,M.;Nagahisa,A.;Nakane,M.;Wiesner,J.B.;Erion,M.D.,Adenosine kinase inhibitors.5.Synthesis,enzyme inhibition,and analgesic activity of diaryl-erythro-furanosyltubercidin analogues.Journal of Medicinal Chemistry 2005,48,(20),6430-6441.
73.Caldwell,J.J.;Davies,T.G.;Doiiald,A.R.R.;McHardy,T.;Rowlands,M.G.;Aherne,G.W.;Hlinter,L.K.;Taylor,K.;Ruddle,R.;Raynaud,F.I.;Verdonk,M.;Workman,P.;Garrett,M.D.;Collins,I.,Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.Journal of Medicinal Chemistry 2008,51,(7),2147-2157.
74.Chen,S.B.;Hilcove,S.;Ding,S.,Exploring stem cell biology with small molecules.Molecular Biosystems 2006,2,(1),18-24.
75．张晶；韩伟，化学分子在干细胞生物学研究中的应用．生命的化学 2007，27，(6)，487-489．
76．赵阳；丁丽娜；苗俊英，小分子化合物在干细胞定向分化诱导研究中的应用．生物医学工程研究 2006，25，(1)，58-61．
77.Ding,S.;Schultz,P.G.,A role for chemistry in stem cell biology.Nature Biotechnology 2004,22,(7),833-840.
78.Chen,S.B.;Do,J.T.;Zhang,Q.S.;Yao,S.Y.;Yan,F.;Peters,E.C.;Scholer,H.R.;Schultz,P.G.;Ding,S.,Self-renewal of embryonic stem cells by a small molecule.Proceedings of the National Academy of Sciences of the United States of America 2006,103,(46),17266-17271.
79.Chen,S.B.;Takanashi,S.C.;Zhang,Q.S.;Xiong,W.;Zhu,S.T.;Peters,E.C.;Ding,S.;Schultz,P.G.,Reversine increases the plasticity of lineage-committed mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 2007,104,(25),10482-10487.
80.Compton,D.R.;Sheng,S.B.;Carlson,K.E.;Rebacz,N.A.;Lee,I.Y.;Katzenellenbogen,B.S.;Katzenellenbogen,J.A.,Pyrazolo[1,5-a]pyrimidines:Estrogen receptor ligands possessing estrogen receptor beta antagonist activity.Journal of Medicinal Chemistry 2004,47,(24),5872-5893.
81.Selleri,S.;Bruni,F.;Costagli,C.;Costanzo,A.;Guerrini,G.;Ciciani,G.;Gratteri,P.;Bonaccini,C.;Aiello,P.M.;Besnard,F.;Renard,S.;Costa,B.;Martini,C.,Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-alpha]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha(1) selective ligands.Journal of Medicinal Chemistry 2003,46,(2),310-313.
82.Widdowson,K.L.;Elliott,J.D.;Veber,D.F.;Nie,H.;Rutledge,M.C.;McCleland,B.W.;Xiang,J.N.;Jurewicz,A.J.;Hertzberg,R.P.;Foley,J.J.;Griswold,D.E.;Martin,L.;Lee,J.M.;White,J.R.;Sarau,H.M.,Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor.Journal of Medicinal Chemistry 2004,47,(6),1319-1321.
83.Sznaidman,M.L.;Meade,E.A.;Beauchamp,L.M.;Russell,S.;Tisdale,M.,The antiinfluenza activity of pyrrolo[2,3-d]pyrimidines.Bioorganic & Medicinal Chemistry Letters 1996,6,(5),565-568.
84.Huang,C.Q.;Wilcoxen,K.M.;Grigoriadis,D.E.;McCarthy,J.R.;Chen,C.,Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-alpha]pyrimidines as potent CRF1 receptor antagonists.Bioorganic & Medicinal Chemistry Letters 2004,14,(15),3943-3947.
85.Yuan,J.;Gulianello,M.;De Lombaert,S.;Brodbeck,R.;Kieltyka,A.;Hodgetts,K.J.,3-aryl pyrazolo[4,3-d]pyrimidine derivatives:Nonpeptide CRF-1 antagonists.Bioorganic & Medicinal Chemistry Letters 2002,12,(16),PⅡ S0960-894X(02)00358-X.
86.Maeda,Y.;Nakano,M.;Sato,H.;Miyazaki,Y.;Schweiker,S.L.;Smith,J.L.;Truesdale,A.T.,4-Acylamino-6-arylfuro[2,3-d]pyrimidines:potent and selective glycogen synthase kinase-3 inhibitors.Bioorganic & Medicinal Chemistry Letters 2004,14,(15),3907-3911.
87.Bursavich,M.G.;Lombardi,S.;Gilbert,A.M.,Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines.Organic Letters 2005,7,(19),4113-4116.
88.Farrand,L.D.;Adlem,K.Preparation of 2-halopyrimidine derivatives useful for synthesis of complex pyrimidines,comprises reacting 2-chloropyrimidine derivatives with solution of hydrogen halide in acid.EP1411048-A;EP1411048-A1,EP1411048-A EP1411048-A1 21 Apr 2004 C07D-239/30 200430 Pages:7 English.
89.Zhang,H.Q.;Xia,Z.R.;Vasudevan,A.;Djuric,S.W.,Efficient Pd-catalyzed synthesis of 2-arylaminopyrimidines via microwave irradiation. Tetrahedron Letters 2006,47,(28), 4881-4884.
90.Cherng,Y.H.,Efficient nucleophilic substitution reactions of pyrimidyl and pyrazyl halides with nucleophiles,under focused microwave irradiation.Tetrahedron 2002,58,(5),887-890.
91.Makosza,M.;Ostrowski,S.,Reactions of chlorinated pyrimidine derivatives with carbanions bearing nucleophugal groups at the carbanionic center.Polish Journal of Chemistry 2000,74,(10),1355-1361.
92.Gosmini,C.;Nedelec,J.Y.;Perichon,J.,Electrochemical cross-coupling between functionalized aryl halides and 2-chloropyrimidine or 2-chloropyrazine catalyzed by nickel 2,2'-bipyridine complex.Tetrahedron Letters 2000,41,(2),201-203.
93.Mosquera,A.;Riveiros,R.;Sestelo,J.P.;Sarandeses,L.A.,Cross-coupling reactions of indium organometallics with 2,5-dihalopyrimidines:Synthesis of hyrtinadine A.Organic Letters 2008,10,(17),3745-3748.
94.Boarland,M.P.V.;McOmie,J.F.W.,Monosubstituted Pyrimidines,and the Action of Thiourea on Chloropyrimidines.Journal of the Chemical Society 1951,(MAY),1218-1221.
95.Kanuma,K.;Omodera,K.;Nishiguchi,M.;Funakoshi,T.;Chaki,S.;Semple,G.;Tran,T.A.;Kramer,B.;Hsu,D.;Casper,M.;Thomsen,B.;Beeley,N.;Sekiguchi,Y.,Discovery of 4-(dimethylamino)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1.Bioorganic & Medicinal Chemistry Letters 2005,15,(10),2565-2569.
96.Breshears,S.R.;Wang,S.S.;Bechtolt,S.G.;Christensen,B.E.,Purines.8.the Aminolysis of Certain Chlorosubstituted Purines.Journal of the American Chemical Society 1959,81,(14),3789-3792.
97.Butters,M.;Ebbs,J.;Green,S.P.;MacRae,J.;Morland,M.C.;Murtiashaw,C.W.;Pettman,A.J.,Process development of voriconazole:A novel broad-spectrum triazole antifungal agent.Organic Process Research & Development 2001,5,(1),28-36.
98.Langli,G.; Gundersen,L. L.;Rise,F.,Regiochemistry in Stille couplings of 2,6-dihalopurines.Tetrahedron 1996,52,(15),5625-5638.
99.Gundersen,L.-L.;Langli,G.;Kseb,F.,Regioselective Pd-Mediated Coupling between 2,6-Dichloropurines and Organometallic Reagents Tetrahedron Letters 1995, 36, (11),1945-1948.
100.Girgis,N.S.;Cottam,H.B.;Larson,S.B.;Robins,R.K.,9-Deazapurine Nucleosides-the Synthesis of Certain N-5-2'-Deoxy-Beta-D-Erythropentofuranosyl and N-5-Beta-D-Arabinofuranosylpyrrolo[3,2-D]Pyrimidines.Journal of Heterocyclic Chemistry 1987,24,(3),821-827.
101.Shuttleworth,S.J.;Folkes,A.J.;Chuckowree,I.S.;Wan,N.C.;Hancox,T.C.;Baker,S.J.;Sohal,S.;Latif,M.A.New fused pyrimidine compounds are phosphatidylinositol 3-kinase inhibitors useful e.g.to treat immune disorders,cardiovascular disease,viral infection,inflammation, metabolism or endocrine disorders and neurological disorders.WO2006046040-A 1;EP 1812446-A 1;JP2008517894-W,2006.
102.Deruiter,J.;Brubaker,A.N.;Millen,J.;Riley,T.N.,Design and Synthesis of 2-(Arylamino)-4(3h)-Quinazolinones as Novel Inhibitors of Rat Lens Aldose Reductase.Journal of Medicinal Chemistry 1986,29,(5),627-629.
103.Ram,V.J.;Farhanullah;Tripathi,B.K.;Srivastava,A.K.,Synthesis and antihyperglycemic activity of suitably functionalized 3H-quinazolin-4-ones.Bioorganic & Medicinal Chemistry 2003,11,(11),2439-2444.
104.Banerjee,A.K.,5'-Terminal Cap Structure in Eukaryotic Messenger Ribonucleic-Acids.Microbiological Reviews 1980,44,(2),175-205.
105.Ueland,P.M.;Helland,S.;Broch,O.J.;Schanche,J.S.,Homocysteine in Tissues of the Mouse and Rat.Journal of Biological Chemistry 1984,259,(4),2360-2364.
106.Chiang,P.K.;Gordon,R.K.;Tal,J.;Zeng,G.C.;Doctor,B.P.;Pardhasaradhi,K.;McCann,P.P.,S-adenosylmethionine and methylation.Faseb Journal 1996,10,(4),471-480.
107.Allison,A.C.,Immunosuppressive drugs,the first 50 years and a glance forward.Immunopharmacology 2000,47,(2-3),63-83.
108.Saso,Y.;Conner,E.M.;Teegarden,B.R.;Yuan,C.S.,S-adenosyl-L-homocysteine hydrolase inhibitor mediates immunosuppressive effects in vivo:Suppression of delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis.Journal of Pharmacology and Experimental Therapeutics 2001,296,(1),106-112.
109.Wu,Q.L.;Fu,Y.F.;Zhou,W.L.;Wang,J.X.;Feng,Y.H.;Liu,J.;Xu,J.Y.;He,P.L.;Zhou,R.;Tang,W.;Wang,G.F.;Zhou,Y.;Yang,Y.F.;Ding,J.;Li,X.Y.;Chen,X.R.;Yuan,C.;Lawson,B.R.;Zuo,J.P.,Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression.J Pharmacol Exp Ther 2005,313,(2),705-11.
110.German,D.C.;Bloch,C.A.;Kredich,N.M.,Measurements of S-Adenosylmethionine and L-Homocysteine Metabolism in Cultured Human Lymphoid-Cells.Journal of Biological Chemistry 1983,258,(18),997-1003.
111.Wolos,J.A.;Frondorf,K.A.;Davis,G.F.;Jarvi,E.T.;McCarthy,J.R.;Bowlin,T.L.,Selective-Inhibition of T-Cell Activation by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase.Journal of Immunology 1993,150,(8),3264-3273.
112.Lambert,L.E.;Frondorf,K.A.;Berling,J.S.;Wolos,J.A.,Effects of an S-Adenosyl-L-Homocysteine Hydrolase Inhibitor on Murine Macrophage Activation and Function.Immunopharmacology 1995,29,(2),121-127.
113.Wolos,J.A.;Frondorf,K.A.;Babcock,G.F.;Stripp,S.A.;Bowlin,T.L., Immunomodulation by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase-Inhibition of in-Vitro and in-Vivo Allogeneic Responses.Cellular Immunology 1993,149,(2),402-408.
114.Wolos,J.A.;Frondorf,K.A.;Esser,R.E.,Immunosuppression Mediated by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase-Prevention and Treatment of Collagen-Induced Arthritis.Journal of Immunology 1993,151,(1),526-534.
115.Zuo,J.;Yuan,C.;Wu,Q.Use of DZ2002 as an immunosuppressive.CN1565453-A;CN 100345545-C,2005.
116.Takahashi,K.;Yoshihisa,S.;Suita;Toyounaka,H.;Takatsuki,S.Adenine Drivative.1971.
117.Holy,A.,Studies on S-Adenosyl-L-Homocysteine Hydrolase.8.Preparation of Isomeric 3-Aminopropylamino Derivatives of “9-(Rs)-(2,3-Dihydroxypropyl)Adenine.Collection of Czechoslovak Chemical Communications 1983,48,(7),1910-1921.
118.Holy, A., Studies on S-Adenosyl-L-Homocysteine Hydrolase .6. Preparation of Enantiomeric and Racemic 2,3,4,5-Tetrahydroxypentyl Derivatives of Adenine,Cytosine and Uracil.Collection of Czechoslovak Chemical Communications 1982,47,(10),2786-2805.
119.Votruba,I.;Holy,A.,Inhibition of S-Adenosyl-L-Homocysteine Hydrolase by the Aliphatic Nucleoside Analog-9-(S)-(2,3-Dihydroxypropyl)Adenine.Collection of Czechoslovak Chemical Communications 1980,45,(11),3039-3044.
120.Cihak, A.; Holy, A., Distribution and Metabolic Transformation of "9-(S)-(2,3-Dihydroxypropyl)Adenine,an Effective Virostatic Agent,in Mice.Collection of Czechoslovak Chemical Communications 1978,43,(8),2082-2088.
121.Holy,A.;Sorm,F.,Nucleic Acid Components and Their Analogues.129.Synthesis of Enantiomeric 2',3'-Cyclic Phosphates of 9-(Alpha-Lyxofuranosyl)Adenine and-Hypoxanthine,and Their Behaviour Towards Ribonuclease T1 and T2.Collection of Czechoslovak Chemical Communications 1969,34,(11),3523-&.
122.Anonymous;Yuan,C.-S.Reversible inhibitors of SAH hydrolase and uses thereof.US 07196093,2007.
123.Denmark,S.E.;Yang,S.M.,Total synthesis of (+)-brasilenyne.Application of an intramolecular silicon-assisted cross-coupling reaction.Journal of the American Chemical Society 2004,126,(39),12432-12440.
124.Fkyerat,A.;Demeunynck,M.;Constant,J.F.;Michon,P.;Lhomme,J.,A New Class of Artificial Nucleases That Recognize and Cleave Apurinic Sites in DNA with Great Selectivity and Efficiency.Journal of the American Chemical Society 1993,115,(22),9952-9959.
125.Ciapetti,P.;Taddei,M.,A simple preparation of N-vinyl derivatives of DNA nucleobases.Tetrahedron 1998,54,(37),11305-11310.
126.Ali,I.;Aboul-Enein,H.Y.;Ghanem,A.,Enantioselective toxicity and carcinogenesis. Current PharmaceuticalAnalysis 2005,1,(1),109-125.
127.Lira,E.P.;Huffrnan,C.W.,Some Michael-Type Reactions with Adenine.Journal of Organic Chemistry 1966,31,(7),2188-&.
128.Burling,S.;Paine,B.M.;Nama,D.;Brown,V.S.;Mahon,M.F.;Prior,T.J.;Pregosin,P.S.;Whittlesey,M.K.;Williams,J.M.J.,C-H activation reactions of ruthenium N-heterocyclic carbene complexes:Application in a catalytic tandem reaction involving C-C bond formation from alcohols.Journal of the American Chemical Society 2007,129,(7),1987-1995.
129.Lozada-Ramirez,J.D.;Martinez-Martinez,I.;Sanchez-Ferrer,A.;Garcia-Carmona,F.,A colorimetric assay for S-adenosylhomocysteine hydrolase.Journal of Biochemical and Biophysical Methods 2006,67,(2-3),131-140.
130.Yang,X.D.;Hu,Y.B.;Yin,D.H.;Turner,M.A.;Wang,M.;Borchardt,R.T.;Howell,P.L.;Kuczera,K.;Schowen,R.L.,Catalytic strategy of S-adenosyl-L-homocysteine hydrolase:Transition-state stabilization and the avoidance of abortive reactions.Biochemistry 2003,42,(7),1900-1909.
2． 邹栩；顾凯，世界新药研发动向．中国新药杂志2007，16，(22)，1821-1826．
3. Severinsen,R.;Bourne,G.T.;Tran,T.T.;Ankersen,M.;Begtrup,M.;Smythe,M.L.,Library of biphenyl privileged substructures using a safety-catch linker approach.Journal of Combinatorial Chemistry 2008,10,(4),557-566.
4. Rouhi,A.M.,Rediscovering natural products.Chemical & Engineering News 2003,81,(41),77.
5. Newman,D.J.,Natural products as leads to potential drugs:An old process or the new hope for drug discovery? Journal of Medicinal Chemistry 2008,51,(9),2589-2599.
6. Henkel,T.;Brunne,R.M.;Muller,H.;Reichel,F.,Statistical investigation into the structural complementarity of natural products and synthetic compounds.Angewandte Chemie-International Edition 1999,38,(5),643-647.
7. Evans,B.E.;Rittle,K.E.;Bock,M.G.;Dipardo,R.M.;Freidinger,R.M.;Whitter,W.L.;Lundell,G.F.;Veber,D.F.;Anderson,P.S.;Chang,R.S.L.;Lotti,V.J.;Cerino,D.J.;Chen,T.B.;Kling,P.J.;Kunkel,K.A.;Springer,J.P.;Hirshfield,J.,Methods for Drug Discovery-Development of Potent,Selective,Orally Effective Cholecystokinin Antagonists.Journal of Medicinal Chemistry 1988,31,(12),2235-2246.
8. Andrews,P.R.;Lloyd,E.J.,Molecular-Conformation and Biological-Activity of Central Nervous-System Active-Drugs.Medicinal Research Reviews 1982,2,(4),355-393.
9. Liu,J.F.;Wilson,C.J.;Ye,P.;Sprague,K.;Sargent,K.;Si,Y.;Beletsky,G.;Yohannes,D.;Ng,S.C.,Privileged structure-based quinazolinone natural product-templated libraries:Identification of novel tubulin polymerization inhibitors.Bioorganic & Medicinal Chemistry Letters 2006,16,(3),686-690.
10.Rheault,T.R.;Caferro,T.R.;Dickerson,S.H.;Donaldso,K.H.;Gaul,M.D.;Goetz,A.S.;Mullin,R.J.;McDonald,O.B.;Petrov,K.G.;Rusnak,D.W.;Shewchuk,L.M.;Spehar,G.M.;Truesdale,A.T.;Vanderwall,D.E.;Wood,E.R.;Uehling,D.E.,Thienopyrimidine-based dual EGFR/ErbB-2 inhibitors.Bioorganic & Medicinal Chemistry Letters 2009,19,(3),817-820.
11．邓世明；林强，新药研究思路与方法．人民卫生出版社：2008．
12．李钧，最新药品注册技术精讲(第二版)．化学工业出版社：2008．
13.Yuan,C.S.;Saso,Y.;Lazarides,E.;Borchardt,R.T.;Robins,M.J.,Recent advances in S-adenosyl-L-homocysteine hydrolase inhibitors and their potential clinical applications.Expert Opinion on Therapeutic Patents 1999,9,(9),1197-1206.
14．付云峰．可逆性S-腺苷同型半胱氨酸水解酶抑制剂(DZ2002)的免疫抑制活性及其作用机制的研究．中科院上海药物研究所，2006．
15．付任重．新型嘧啶并环分子的设计与合成．吉林大学，2008．
16.Kompis,I.M.;Islam,K.;Then,R.L.,DNA and RNA synthesis:Antifolates.Chemical Reviews 2005,105,(2),593-620.
17.Gangjee,A.;Shi,J.F.;Queener,S.F.,Synthesis and biological activities of conformationally restricted,tricyclic nonclassical antifolates as inhibitors of dihydrofolate reductases.Journal of Medicinal Chemistry 1997,40,(12),1930-1936.
18.McGuire,J.J.,Anticancer antifolates:Current status and furture directions.Current Pharmaceutical Design 2003,9,(31),2593-2613.
19.Ridley,R.G,Medical need,scientific opportunity and the drive for antimalarial drugs.Nature 2002,415,(6872),686-693.
20.Gangjee,A.;Qiu,Y.B.;Li,W.;Kisliuk,R.L.,Potent dual thymidylate synthase and dihydrofolate reductase inhibitors: Classical and nonclassical 2-amino-4-oxo-5-arylthio-substituted-6-methylthieno[2,3-d]pyrimidine Antifolates.Journal of Medicinal Chemistry 2008,51,(18),5789-5797.
21.Gangjee,A.;Li,W.;Yang,J.;Kisliuk,R.L.,Design,synthesis,and biological evaluation of classical and nonclassical 2-amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as dual thymidylate synthase and dihydrofolate reductase inhibitors.Journal of Medicinal Chemistry 2008,51,(1),68-76.
22.Gangjee,A.;Jain,H.D.;Queener,S.F.;Kisliuk,R.L.,The effect of 5-alkyl modification on the biological activity of pyrrolo[2,3-d]pyrimidine containing classical and nonclassical antifolates as inhibitors of dihydrofolate reductase and as antitumor and/or antiopportunistic infection agents.Journal of Medicinal Chemistry 2008,51,(15),4589-4600.
23.Gangjee,A.;Zeng,Y.B.;Talreja,T.;McGuire,J.J.;Kisliuk,R.L.;Queener,S.F.,Design and synthesis of classical and nonclassical 6-arylthio-2,4-diamino-5-ethylpyrrolo[2,3-d]pyrimidines as antifolates.Journal of Medicinal Chemistry 2007,50,(13),3046-3053.
24.Gangjee,A.;Jain,H.D.;Phan,J.;Lin,X.;Song,X.H.;McGuire,J.J.;Kisliuk,R.L.,Dual inhibitors of thymidylate synthase and dihydrofolate reductase as antitumor agents:Design,synthesis,and biological evaluation of classical and nonclassical pyrrolo[2,3-d]pyrimidine antifolates.Journal of Medicinal Chemistry 2006,49,(3),1055-1065.
25.Fredholm,B.B.;Chen,J.F.;Cunha,R.A.;Svenningsson,P.;Vaugeois,J.M.,Adenosine and brain function.International Review ofNeurobiology,Vol 63 2005,63,191-270.26.Fredholm,B.B.;Cunha,R.A.;Svenningsson,P.,Pharmacology of adenosine A(2A) receptors and therapeutic applications.Current Topics in Medicinal Chemistry 2003,3,(4),413-426.
27.Fredholm,B.B.;Ijzerman,A.P.;Jacobson,K.A.;Klotz,K.N.;Linden,J.,International Union of Pharmacology.XXV.Nomenclature and classification of adenosine receptors.Pharmacological Reviews 2001,53,(4),527-552.
28.Akkari,R.;Burbiel,J.C.;Hockemeyer,J.;Muller,C.E.,Recent progress in the development of adenosine receptor ligands as antiinflammatory drugs.Current Topics in Medicinal Chemistry 2006,6,(13),1375-1399.
29.Joshi,B.V.;Jacobson,K.A.,Purine derivatives as ligands for A(3) adenosine receptors.Current Topics in Medicinal Chemistry 2005,5,(13),1275-1295.
30.Press,N.J.;Keller,T.H.;Tranter,P.;Beer,D.;Jones,K.;Faessler,A.;Heng,R.H.;Lewis,C.;Howe,T.;Gedeck,P.;Mazzoni,L.;Fozard,J.R.,New highly potent and selective adenosine A(3) receptor antagonists.Current Topics in Medicinal Chemistry 2004,4,(8),863-870.
31.Cacciari,B.;Pastorin,G.;Spalluto,G.,Medicinal chemistry of A2A adenosine receptor antagonists.Current Topics in Medicinal Chemistry 2003,3,(4),403-411.
32.Cristalli,G.;Lambertucci,C.;Taffi,S.;Vittori,S.;Volpini,R.,Medicinal chemistry of adenosine A(2A) receptor agonists.Current Topics in Medicinal Chemistry 2003,3,(4),387-401.
33.Webb,R.L.;Sills,M.A.;Chovan,J.P.;Balwierczak,J.L.;Francis,J.E.,Cgs-21680-a Potent Selective Adenosine A2 Receptor Agonist.Cardiovascular Drug Reviews 1992,10,(1),26-53.
34.Francis,J.E.;Cash,W.D.;Barbaz,B.S.;Bernard,P.S.;Lovell,R.A.;Mazzenga,G.C.;Friedmann,R.C.;Hyun,J.L.;Braunwalder,A.F.;Loo,P.S.;Bennett,D.A.,Synthesis and Benzodiazepine Binding-Activity of a Series of Novel[1,2,4]Triazolo[1,5-C]Quinazolin-5(6h)-Ones.Journal of Medicinal Chemistry 1991,34,(1),281-290.
35.Francis,J.E.;Webb,R.L.;Ghai,G.R.;Hutchison,A.J.;Moskal,M.A.;Dejesus,R.;Yokoyama,R.;Rovinski,S.L.;Contardo,N.;Dotson,R.;Barclay,B.;Stone,G.A.;Jarvis,M.F.,Highly Selective Adenosine-A2 Receptor Agonists in a Series of N-Alkylated 2-Aminoadenosines.Journal of Medicinal Chemistry 1991,34,(8),2570-2579.
36.Francis,J.E.;Cash,W.D.;Psychoyos,S.;Ghai,G.;Wenk,P.;Friedmann,R.C.;Atkins,C.;Warren,V.;Furness,P.;Hyun,J.L.;Stone,G.A.;Desai,M.;Williams,M.,Structure Activity Profile of a Series of Novel Triazoloquinazoline Adenosine Antagonists.Journal of Medicinal Chemistry 1988,31,(5),1014-1020.
37.Ghai,G.;Francis,J.E.;Williams,M.;Dotson,R.A.;Hopkins,M.F.;Cote,D.T.;Goodman,F.R.;Zimmerman,M.B.,Pharmacological Characterization of Cgs-15943a-a Novel Nonxanthine Adenosine Antagonist.Journal of Pharmacology and Experimental Therapeutics 1987,242,(3),784-790.
38.Cosimelli,B.;Greco,G.;Ehlardo,M.;Novellino,E.;Da Settimo,F.;Taliani,S.;La Motta,C.;Bellandi,M.;Tuccinardi,T.;Martinelli,A.;Ciampi,O.;Trincavelli,M.L.;Martini,C.,Derivatives of 4-amino-6-hydroxy-2-mercaptopyrimidine as novel,potent,and selective A(3) adenosine receptor antagonists.Journal of Medicinal Chemistry 2008,51,(6),1764-1770.
39.Kalla,R.V.;Elzein,E.;Perry,T.;Li,X.F.;Palle,V.;Varkhedkar,V.;Gimbel,A.;Maa,T.;Zeng,D.W.;Zablocki,J.,Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines:High affinity and selective A(2B) adenosine receptor antagonists.Journal of Medicinal Chemistry 2006,49,(12),3682-3692.
40.Chang,L.C.W.;Spanjersberg,R.F.;Kunzel,J.;Brussee,J.;Ijzerman,A.P.,2,6-disubstituted and 2,6,8-trisubstituted purines as adenosine receptor antagonists.Journal of Medicinal Chemistry 2006,49,(10),2861-2867.
41.Lanier,M.C.;Moorjani,M.;Luo,Z.Y.;Chen,Y.S.;Lin,E.;Tellew,J.E.;Zhang,X.H.;Williams,J.P.;Gross,R.S.;Lechner,S.M.;Markison,S.;Joswig,T.;Kargo,W.;Piercey,J.;Santos,M.;Malany,S.;Zhao,M.;Petroski,R.;Crespo,M.I.;Diaz,J.L.;Saunders,J.;Wen,J.;O'Brien, Z.; Jalali, K.; Madan, A.; Slee, D. H.,N-[6-Amino-2-(heteroaryl)pyrimidin-4-yl]acetamides as A(2A) Receptor Antagonists with Improved Drug Like Properties and in Vivo Efficacy.Journal of Medicinal Chemistry 2009,52,(3),709-717.
42.Slee,D.H.;Zhang,X.H.;Moorjani,M.;Lin,E.;Lanier,M.C.;Chen,Y.S.;Rueter,J.K.;Lechner,S.M.;Markison,S.;Malany,S.;Joswig,T.;Santos,M.;Gross,R.S.;Williams,J.P.;Castro-Palomino,J.C.;Crespo,M.I.;Prat,M.;Gual,S.;Diaz,J.L.;Wen,J.;O'Brien,Z.;Saunders,J.,Identification of novel,water-soluble,2-amino-N-pyrimidin-4-yl acetamides as A(2A) receptor antagonists with in vivo efficacy.Journal of Medicinal Chemistry 2008,51,(3),400-406.
43.Slee,D.H.;Chen,Y.;Zhang,X.H.;Moorjani,M.;Lanier,M.C.;Lin,E.;Rueter,J.K.;Williams,J.P.;Lechner,S.M.;Markison,S.;Malany,S.;Santos,M.;Gross,R.S.;Jalali,K.;Sai,Y.;Zuo,Z.Y.;Yang,C.;Castro-Palomino,J.C.;Crespo,M.I.;Prat,M.;Gual,S.;Diaz,J.L.;Saunders, J., 2-amino-N-pyrimidin-4-ylacetamides as A(2A) receptor antagonists: 1.Structure-activity relationships and optimization of heterocyclic substituents.Journal of Medicinal Chemistry 2008,51,(6),1719-1729.
44.Zhang,X.H.;Tellew,J.E.;Luo,Z.Y.;Moorjani,M.;Lin,E.;Lanier,M.C.;Chen,Y.;Williams,J.P.;Saunders,J.;Lechner,S.M.;Markison,S.;Joswig,T.;Petroski,R.;Piercey,J.;Kargo,W.;Malany,S.;Santos,M.;Gross,R.S.;Wen,J.;Jalali,K.;O'Brien,Z.;Stotz,C.E.; Crespo, M. I.; Diaz, J. L.; Slee, D. H., Lead Optimization of 4-Acetylamino-2-(3,5-dimethylpyrazol-l-yl)-6-pyridylpyrimidines as A(2A) Adenosine Receptor Antagonists for the Treatment of Parkinson's Disease.Journal of Medicinal Chemistry 2008,51,(22),7099-7110.
45.Morizzo,E.;Capelli,F.;Lenzi,O.;Catarzi,D.;Varano,F.;Filacchioni,G.;Vincenzi,F.;Varani,K.;Borea,P.A.;Colotta,V.;Moro,S.,Scouting human A(3) adenosine receptor antagonist binding mode using a molecular simplification approach:From triazoloquinoxaline to a pyrimidine skeleton as a key study.Journal of Medicinal Chemistry 2007,50,(26),6596-6606.
46.Gillespie,R.J.;Bamford,S.J.;Botting,R.;Comer,M.;Denny,S.;Gaur,S.;Griffin,M.;Jordan,A.M.;Knight,A.R.;Lerpiniere,J.;Leonardi,S.;Lightowler,S.;McAteer,S.;Merrett,A.;Misra,A.;Padfield,A.;Reece,M.;Saadi,M.;Selwood,D.L.;Stratton,G.C.;Surry,D.;Todd,R.;Tong,X.;Ruston,V.;Upton,R.;Weiss,S.M.,Antagonists of the Human A(2A)Adenosine Receptor. 4. Design, Synthesis, and Preclinical Evaluation of 7-Aryltriazolo[4,5-d]pyrimidines.Journal of Medicinal Chemistry 2009,52,(1),33-47.
47.Neustadt,B.R.;Liu,H.;Hao,J.S.;Greenlee,W.J.;Stamford,A.W.;Foster,C.;Arik,L.;Lachowicz,J.;Zhang,H.T.;Bertorelli,R.;Fredduzzi,S.;Varty,G.;Cohen-Williams,M.;Ng,K.,Potent and selective adenosine A(2A) receptor antagonists:1,2,4-Triazolo[1,5-c]pyrimidines.Bioorganic & Medicinal Chemistry Letters 2009,19,(3),967-971.
48.Sharma,P.S.;Sharma,R.;Tyagi,T.,Receptor Tryosine Kinase Inhibitors as Potent Weapons in War Against Cancers.Current Pharmaceutical Design 2009,15,(7),758-776.
49.Akritopoulou-Zanze,I.;Hajduk,P.J.,Kinase-targeted libraries:The design and synthesis of novel,potent,and selective kinase inhibitors.Drug Discovery Today 2009,14,(5-6),291-297.
50.Gilfillan,A.M.;Rivera,J.,The tyrosine kinase network regulating mast cell activation.Immunological Reviews 2009,228,149-169.
51.Grant,S.,Therapeutic Protein Kinase Inhibitors.Cellular and Molecular Life Sciences 2009,66,(7),1163-1177.
52.Bridges,A.J.,Chemical inhibitors of protein kinases.Chemical Reviews 2001,101,(8),2541-2571.
53.Showalter,H.D.H.;Bridges,A.J.;Zhou,H.R.;Sercel,A.D.;McMichael,A.;Fry,D.W.,Tyrosine kinase inhibitors. 16. 6,5,6-tricyclic benzothieno[3,2-d]pyrimidines and pyrimido[5,4-b]-and-[4,5-b]indoles as potent inhibitors of the epidermal growth factor receptor tyrosine kinase.Journal of Medicinal Chemistry 1999,42,(26),5464-5474.
54.Kiselyov,A.S.;Smith,L.,Novel one pot synthesis of polysubstituted pyrazolo[1,5-a]-and imidazo[1,2-a]pyrimidines.Tetrahedron Letters 2006,47,(15),2611-2614.
55.Smith,L.;Piatnitski,E.L.;Kiselyov,A.S.;Ouyang,X.;Chen,X.L.;Burdzovic-Wizemann, S.;Xu,Y.J.;Wang,Y.;Rosler,R.L.;Patel,S.N.;Chiang,H.H.;Millign,D.L.;Columbus,J.;Wong, W. C.; Doody, J. F.; Hadari, Y. R., Tricyclic azepine derivatives:Pyrimido[4,5-b]-l,4-benzoxazepines as a novel class of epidermal growth factor receptor kinase inhibitors.Bioorganic & Medicinal Chemistry Letters 2006,16,(6),1643-1646.
56.Smith,L.;Wong,W.C.;Kiselyov,A.S.;Burdzovic-Wizemann,S.;Mao,Y.Y.;Xu,Y.J.;Duncton,M.A.J.;Kim,K.;Piatnitski,E.L.;Doody,J.F.;Wang,Y.;Rosler,R.L.;Milligan,D.;Columbus,J.;Balagtas,C.;Lee,S.P.Konovalov,A.;Hadari,Y.R.,Novel tricyclic azepine derivatives:Biological evaluation of pyrimido[4,5-b]-1,4-benzoxazepines,thiazepines,and diazepines as inhibitors of the epidermal growth factor receptor tyrosine kinase.Bioorganic & Medicinal Chemistry Letters 2006,16,(19),5102-5106.
57.Smaill,J.B.;Rewcastle,G.W.;Loo,J.A.;Greis,K.D.;Chan,O.H.;Reyner,E.L.;Lipka,E.;Showalter,H.D.H.;Vincent,P.W.;Elliott,W.L.;Denny,W.A.,Tyrosine kinase inhibitors.17.Irreversible inhibitors of the epidermal growth factor receptor:4-(phenylamino)quinazoline-and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions.Journal of Medicinal Chemistry 2000,43,(7),1380-1397.
58.Smaill,J.B.;Rewcastle,G.W.;Bridges,A.J.;Zhou,H.R.;Showalter,H.D.H.;Fry,D.W.;Nelson,J.M.;Sherwood,V.;Elliott,W.L.;Vincent,P.W.;DeJohn,D.E.;Loo,J.A.;Greis,K.D.;Chan,O.H.;Reyner,E.L.;Lipka,E.;Denny,W.A.,Tyrosine kinase inhibitors.17.Irreversible inhibitors of the epidermal growth factor receptor:4-(phenylamino)quinazoline-and 4-(phenylamino)pyrido[3,2-d]-pyrimidine-6-acrylamides bearing additional solubilizing functions (vol 43,pg 1380,2000).Journal of Medicinal Chemistry 2000,43,(16),3199-3199.
59.Rewcastle,G.W.;Murray,D.K.;Elliott,W.L.;Fry,D.W.;Howard,C.T.;Nelson,J.M.;Roberts,B.J.;Vincent,P.W.;Showalter,H.D.H.;Winters,R.T.;Denny,W.A.,Tyrosine kinase inhibitors.14.Structure-activity relationships for methylamino-substituted derivatives of 4-[(3-bromophenyl)amino]-6-(methylamino)pyrido[3,4-d]pyrimidine (PD 158780),a potent and specific inhibitor of the tyrosine kinase activity of receptors for the EGF family of growth factors.Journal of Medicinal Chemistry 1998,41,(5),742-751.
60.Rewcastle,G.W.;Bridges,A.J.;Fry,D.W.;Rubin,J.R.;Denny,W.A.,Tyrosine kinase inhibitors .12. Synthesis and structure-activity relationships for 6-substituted 4-(phenylamino)pyrimido[5,4-d]pyrimidines designed as inhibitors of the epidermal growth factor receptor.Journal of Medicinal Chemistry 1997,40,(12),1820-1826.
61.Rewcastle,G.W.;Palmer,B.D.;Thompson,A.M.;Bridges,A.J.;Cody,D.R.;Zhou,H.R.;Fry,D.W.;McMichael,A.;Denny,W.A.,Tyrosine kinase inhibitors.10.Isomeric 4-[(3-bromophenyl)amino]pyrido[d]-pyrimidines are potent ATP-binding site inhibitors of the tyrosine kinase function of the epidermal growth factor receptor.Journal of Medicinal Chemistry 1996,39,(9),1823-1835.
62.Manetti,F.;Brullo,C.;Magnani,M.;Mosci,F.;Chelli,B.;Crespan,E.;Schenone,S.;Naldini,A.;Bruno,O.;Trincavelli,M.L.;Maga,G.;Carraro,F.;Martini,C.;Bondavalli,F.;Bottat,M.,Structure-based optimization of pyrazolo[3,4-d]pyrimidines as Abl inhibitors and antiproliferative agents toward human leukemia cell lines.Journal of Medicinal Chemistry 2008,51,(5),1252-1259.
63.Echalier,A.;Bettayeb,K.;Ferandin,Y.;Lozach,O.;Clement,M.;Valette,A.;Liger,F.;Marquet, B.; Morris, J. C.; Endicott, J. A.; Joseph, B.; Meijer, L., Meriolins (3-(pyrimidin-4-yl)-7-azaindoles):Synthesis,kinase inhibitory activity,cellular effects,and structure of a CDK2/cyclin A/meriolin complex.Journal of Medicinal Chemistry 2008,51,(4),737-751.
64.Bathini,Y.;Singh,I.;Harvey,P.J.;Keller,P.R.;Singh,R.;Micetich,R.G.;Fry,D.W.;Dobrusin,E.M.;Toogood,P.L.,2-Aminoquinazoline inhibitors of cyclin-dependent kinases.Bioorganic & Medicinal Chemistry Letters 2005,15,(17),3881-3885.
65.Toogood,P.L.;Harvey,P.J.;Repine,J.T.;Sheehan,D.J.;VanderWel,S.N.;Zhou,H.R.;Keller,P.R.;McNamara,D.J.;Sherry,D.;Zhu,T.;Brodfuehrer,J.;Choi,C.;Barvian,M.R.;Fry,D.W.,Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.Journal of Medicinal Chemistry 2005,48,(7),2388-2406.
66.VanderWel,S.N.;Harvey,P.J.;McNamara,D.J.;Repine,J.T.;Keller,P.R.;Quin,J.;Booth, R. J.; Elliott,W. L.; Dobrusin,E. M.; Fry, D. W.;Toogood, P. L.,Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4.Journal of Medicinal Chemistry 2005,48,(7),2371-2387.
67.Gaillard,P.;Jeanclaude-Etter,I.;Ardissone,V.;Arkinstall,S.;Cambet,Y.;Camps,M.;Chabert,C.;Church,D.;Cirillo,R.;Gretener,D.;Halazy,S.;Nichols,A.;Szyndralewiez,C.;Vitte,P.A.;Gotteland,J.P.,Design and synthesis of the first generation of novel potent,selective,and in vivo active (benzothiazol-2-yl)acetonitrile inhibitors of the c-Jun N-terminal kinase.Journal of Medicinal Chemistry 2005,48,(14),4596-4607.
68.Klutchko,S.R.;Zhou,H.R.;Winters,R.T.;Tran,T.P.;Bridges,A.J.;Althaus,I.W.;Amato,D.M.;Elliott,W.L.;Ellis,P.A.;Meade,M.A.;Roberts,B.J.;Fry,D.W.;Gonzales,A.J.;Harvey,P.J.;Nelson,J.M.;Sherwood,V.;Han,H.K.;Pace,G.;Smaill,J.B.;Denny,W.A.;Showalter,H.D.H.,Tyrosine kinase inhibitors.19.6-alkynamides of 4-anilinoquinazolines and 4-anilinopyrido[3,4-d]pyrimidines as irreversible inhibitors of the erbB family of tyrosine kinase receptors.Journal of Medicinal Chemistry 2006,49,(4),1475-1485.
69.Sabat,M.;VanRens,J.C.;Brugel,T.A.;Maier,J.;Laufersweiler,M.J.;Golebiowski,A.;De,B.;Easwaran,V.;Hsieh,L.C.;Rosegen,J.;Berberich,S.;Suchanek,E.;Janusz,M.J.,The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lyrnphocyte specific kinase (Lck).Bioorganic & Medicinal Chemistry Letters 2006,16,(16),4257-42.61.
70.Bookser,B.C.;Matelich,M.C.;Ollis,K.;Ugarkar,B.G.,Adenosine kinase inhibitors.4.6,8-disubstituted purine nucleoside derivatives.Synthesis,conformation,and enzyme inhibition.Journal of Medicinal Chemistry 2005,48,(9),3389-3399.
71.Bookser,B.C.;Ugarkar,B.G.;Matelich,M.C.;Lemus,R.H.;Allan,M.;Tsuchiya,M.;Nakane,M.;Nagahisa,A.;Wiesner,J.B.;Erion,M.D.,Adenosine kinase inhibitors.6.Synthesis,water solubility, and antinociceptive activity of 5-phenyl-7-(5-deoxy-beta-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidines substituted at C4 with glycinamides and related compounds.Journal of Medicinal Chemistry 2005,48,(24),7808-7820.
72.Boyer,S.H.;Ugarkar,B.G.;Solbach,J.;Kopcho,J.;Matelich,M.C.;Ollis,K.;Gomez-Galeno,J.E.;Mendonca,R.;Tsuchiya,M.;Nagahisa,A.;Nakane,M.;Wiesner,J.B.;Erion,M.D.,Adenosine kinase inhibitors.5.Synthesis,enzyme inhibition,and analgesic activity of diaryl-erythro-furanosyltubercidin analogues.Journal of Medicinal Chemistry 2005,48,(20),6430-6441.
73.Caldwell,J.J.;Davies,T.G.;Doiiald,A.R.R.;McHardy,T.;Rowlands,M.G.;Aherne,G.W.;Hlinter,L.K.;Taylor,K.;Ruddle,R.;Raynaud,F.I.;Verdonk,M.;Workman,P.;Garrett,M.D.;Collins,I.,Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.Journal of Medicinal Chemistry 2008,51,(7),2147-2157.
74.Chen,S.B.;Hilcove,S.;Ding,S.,Exploring stem cell biology with small molecules.Molecular Biosystems 2006,2,(1),18-24.
75．张晶；韩伟，化学分子在干细胞生物学研究中的应用．生命的化学 2007，27，(6)，487-489．
76．赵阳；丁丽娜；苗俊英，小分子化合物在干细胞定向分化诱导研究中的应用．生物医学工程研究 2006，25，(1)，58-61．
77.Ding,S.;Schultz,P.G.,A role for chemistry in stem cell biology.Nature Biotechnology 2004,22,(7),833-840.
78.Chen,S.B.;Do,J.T.;Zhang,Q.S.;Yao,S.Y.;Yan,F.;Peters,E.C.;Scholer,H.R.;Schultz,P.G.;Ding,S.,Self-renewal of embryonic stem cells by a small molecule.Proceedings of the National Academy of Sciences of the United States of America 2006,103,(46),17266-17271.
79.Chen,S.B.;Takanashi,S.C.;Zhang,Q.S.;Xiong,W.;Zhu,S.T.;Peters,E.C.;Ding,S.;Schultz,P.G.,Reversine increases the plasticity of lineage-committed mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 2007,104,(25),10482-10487.
80.Compton,D.R.;Sheng,S.B.;Carlson,K.E.;Rebacz,N.A.;Lee,I.Y.;Katzenellenbogen,B.S.;Katzenellenbogen,J.A.,Pyrazolo[1,5-a]pyrimidines:Estrogen receptor ligands possessing estrogen receptor beta antagonist activity.Journal of Medicinal Chemistry 2004,47,(24),5872-5893.
81.Selleri,S.;Bruni,F.;Costagli,C.;Costanzo,A.;Guerrini,G.;Ciciani,G.;Gratteri,P.;Bonaccini,C.;Aiello,P.M.;Besnard,F.;Renard,S.;Costa,B.;Martini,C.,Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-alpha]pyrimidine derivatives. 3. New 6-(3-thienyl) series as alpha(1) selective ligands.Journal of Medicinal Chemistry 2003,46,(2),310-313.
82.Widdowson,K.L.;Elliott,J.D.;Veber,D.F.;Nie,H.;Rutledge,M.C.;McCleland,B.W.;Xiang,J.N.;Jurewicz,A.J.;Hertzberg,R.P.;Foley,J.J.;Griswold,D.E.;Martin,L.;Lee,J.M.;White,J.R.;Sarau,H.M.,Evaluation of potent and selective small-molecule antagonists for the CXCR2 chemokine receptor.Journal of Medicinal Chemistry 2004,47,(6),1319-1321.
83.Sznaidman,M.L.;Meade,E.A.;Beauchamp,L.M.;Russell,S.;Tisdale,M.,The antiinfluenza activity of pyrrolo[2,3-d]pyrimidines.Bioorganic & Medicinal Chemistry Letters 1996,6,(5),565-568.
84.Huang,C.Q.;Wilcoxen,K.M.;Grigoriadis,D.E.;McCarthy,J.R.;Chen,C.,Design and synthesis of 3-(2-pyridyl)pyrazolo[1,5-alpha]pyrimidines as potent CRF1 receptor antagonists.Bioorganic & Medicinal Chemistry Letters 2004,14,(15),3943-3947.
85.Yuan,J.;Gulianello,M.;De Lombaert,S.;Brodbeck,R.;Kieltyka,A.;Hodgetts,K.J.,3-aryl pyrazolo[4,3-d]pyrimidine derivatives:Nonpeptide CRF-1 antagonists.Bioorganic & Medicinal Chemistry Letters 2002,12,(16),PⅡ S0960-894X(02)00358-X.
86.Maeda,Y.;Nakano,M.;Sato,H.;Miyazaki,Y.;Schweiker,S.L.;Smith,J.L.;Truesdale,A.T.,4-Acylamino-6-arylfuro[2,3-d]pyrimidines:potent and selective glycogen synthase kinase-3 inhibitors.Bioorganic & Medicinal Chemistry Letters 2004,14,(15),3907-3911.
87.Bursavich,M.G.;Lombardi,S.;Gilbert,A.M.,Expedient parallel synthesis of 2-amino-4-heteroarylpyrimidines.Organic Letters 2005,7,(19),4113-4116.
88.Farrand,L.D.;Adlem,K.Preparation of 2-halopyrimidine derivatives useful for synthesis of complex pyrimidines,comprises reacting 2-chloropyrimidine derivatives with solution of hydrogen halide in acid.EP1411048-A;EP1411048-A1,EP1411048-A EP1411048-A1 21 Apr 2004 C07D-239/30 200430 Pages:7 English.
89.Zhang,H.Q.;Xia,Z.R.;Vasudevan,A.;Djuric,S.W.,Efficient Pd-catalyzed synthesis of 2-arylaminopyrimidines via microwave irradiation. Tetrahedron Letters 2006,47,(28), 4881-4884.
90.Cherng,Y.H.,Efficient nucleophilic substitution reactions of pyrimidyl and pyrazyl halides with nucleophiles,under focused microwave irradiation.Tetrahedron 2002,58,(5),887-890.
91.Makosza,M.;Ostrowski,S.,Reactions of chlorinated pyrimidine derivatives with carbanions bearing nucleophugal groups at the carbanionic center.Polish Journal of Chemistry 2000,74,(10),1355-1361.
92.Gosmini,C.;Nedelec,J.Y.;Perichon,J.,Electrochemical cross-coupling between functionalized aryl halides and 2-chloropyrimidine or 2-chloropyrazine catalyzed by nickel 2,2'-bipyridine complex.Tetrahedron Letters 2000,41,(2),201-203.
93.Mosquera,A.;Riveiros,R.;Sestelo,J.P.;Sarandeses,L.A.,Cross-coupling reactions of indium organometallics with 2,5-dihalopyrimidines:Synthesis of hyrtinadine A.Organic Letters 2008,10,(17),3745-3748.
94.Boarland,M.P.V.;McOmie,J.F.W.,Monosubstituted Pyrimidines,and the Action of Thiourea on Chloropyrimidines.Journal of the Chemical Society 1951,(MAY),1218-1221.
95.Kanuma,K.;Omodera,K.;Nishiguchi,M.;Funakoshi,T.;Chaki,S.;Semple,G.;Tran,T.A.;Kramer,B.;Hsu,D.;Casper,M.;Thomsen,B.;Beeley,N.;Sekiguchi,Y.,Discovery of 4-(dimethylamino)quinazolines as potent and selective antagonists for the melanin-concentrating hormone receptor 1.Bioorganic & Medicinal Chemistry Letters 2005,15,(10),2565-2569.
96.Breshears,S.R.;Wang,S.S.;Bechtolt,S.G.;Christensen,B.E.,Purines.8.the Aminolysis of Certain Chlorosubstituted Purines.Journal of the American Chemical Society 1959,81,(14),3789-3792.
97.Butters,M.;Ebbs,J.;Green,S.P.;MacRae,J.;Morland,M.C.;Murtiashaw,C.W.;Pettman,A.J.,Process development of voriconazole:A novel broad-spectrum triazole antifungal agent.Organic Process Research & Development 2001,5,(1),28-36.
98.Langli,G.; Gundersen,L. L.;Rise,F.,Regiochemistry in Stille couplings of 2,6-dihalopurines.Tetrahedron 1996,52,(15),5625-5638.
99.Gundersen,L.-L.;Langli,G.;Kseb,F.,Regioselective Pd-Mediated Coupling between 2,6-Dichloropurines and Organometallic Reagents Tetrahedron Letters 1995, 36, (11),1945-1948.
100.Girgis,N.S.;Cottam,H.B.;Larson,S.B.;Robins,R.K.,9-Deazapurine Nucleosides-the Synthesis of Certain N-5-2'-Deoxy-Beta-D-Erythropentofuranosyl and N-5-Beta-D-Arabinofuranosylpyrrolo[3,2-D]Pyrimidines.Journal of Heterocyclic Chemistry 1987,24,(3),821-827.
101.Shuttleworth,S.J.;Folkes,A.J.;Chuckowree,I.S.;Wan,N.C.;Hancox,T.C.;Baker,S.J.;Sohal,S.;Latif,M.A.New fused pyrimidine compounds are phosphatidylinositol 3-kinase inhibitors useful e.g.to treat immune disorders,cardiovascular disease,viral infection,inflammation, metabolism or endocrine disorders and neurological disorders.WO2006046040-A 1;EP 1812446-A 1;JP2008517894-W,2006.
102.Deruiter,J.;Brubaker,A.N.;Millen,J.;Riley,T.N.,Design and Synthesis of 2-(Arylamino)-4(3h)-Quinazolinones as Novel Inhibitors of Rat Lens Aldose Reductase.Journal of Medicinal Chemistry 1986,29,(5),627-629.
103.Ram,V.J.;Farhanullah;Tripathi,B.K.;Srivastava,A.K.,Synthesis and antihyperglycemic activity of suitably functionalized 3H-quinazolin-4-ones.Bioorganic & Medicinal Chemistry 2003,11,(11),2439-2444.
104.Banerjee,A.K.,5'-Terminal Cap Structure in Eukaryotic Messenger Ribonucleic-Acids.Microbiological Reviews 1980,44,(2),175-205.
105.Ueland,P.M.;Helland,S.;Broch,O.J.;Schanche,J.S.,Homocysteine in Tissues of the Mouse and Rat.Journal of Biological Chemistry 1984,259,(4),2360-2364.
106.Chiang,P.K.;Gordon,R.K.;Tal,J.;Zeng,G.C.;Doctor,B.P.;Pardhasaradhi,K.;McCann,P.P.,S-adenosylmethionine and methylation.Faseb Journal 1996,10,(4),471-480.
107.Allison,A.C.,Immunosuppressive drugs,the first 50 years and a glance forward.Immunopharmacology 2000,47,(2-3),63-83.
108.Saso,Y.;Conner,E.M.;Teegarden,B.R.;Yuan,C.S.,S-adenosyl-L-homocysteine hydrolase inhibitor mediates immunosuppressive effects in vivo:Suppression of delayed type hypersensitivity ear swelling and peptidoglycan polysaccharide-induced arthritis.Journal of Pharmacology and Experimental Therapeutics 2001,296,(1),106-112.
109.Wu,Q.L.;Fu,Y.F.;Zhou,W.L.;Wang,J.X.;Feng,Y.H.;Liu,J.;Xu,J.Y.;He,P.L.;Zhou,R.;Tang,W.;Wang,G.F.;Zhou,Y.;Yang,Y.F.;Ding,J.;Li,X.Y.;Chen,X.R.;Yuan,C.;Lawson,B.R.;Zuo,J.P.,Inhibition of S-adenosyl-L-homocysteine hydrolase induces immunosuppression.J Pharmacol Exp Ther 2005,313,(2),705-11.
110.German,D.C.;Bloch,C.A.;Kredich,N.M.,Measurements of S-Adenosylmethionine and L-Homocysteine Metabolism in Cultured Human Lymphoid-Cells.Journal of Biological Chemistry 1983,258,(18),997-1003.
111.Wolos,J.A.;Frondorf,K.A.;Davis,G.F.;Jarvi,E.T.;McCarthy,J.R.;Bowlin,T.L.,Selective-Inhibition of T-Cell Activation by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase.Journal of Immunology 1993,150,(8),3264-3273.
112.Lambert,L.E.;Frondorf,K.A.;Berling,J.S.;Wolos,J.A.,Effects of an S-Adenosyl-L-Homocysteine Hydrolase Inhibitor on Murine Macrophage Activation and Function.Immunopharmacology 1995,29,(2),121-127.
113.Wolos,J.A.;Frondorf,K.A.;Babcock,G.F.;Stripp,S.A.;Bowlin,T.L., Immunomodulation by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase-Inhibition of in-Vitro and in-Vivo Allogeneic Responses.Cellular Immunology 1993,149,(2),402-408.
114.Wolos,J.A.;Frondorf,K.A.;Esser,R.E.,Immunosuppression Mediated by an Inhibitor of S-Adenosyl-L-Homocysteine Hydrolase-Prevention and Treatment of Collagen-Induced Arthritis.Journal of Immunology 1993,151,(1),526-534.
115.Zuo,J.;Yuan,C.;Wu,Q.Use of DZ2002 as an immunosuppressive.CN1565453-A;CN 100345545-C,2005.
116.Takahashi,K.;Yoshihisa,S.;Suita;Toyounaka,H.;Takatsuki,S.Adenine Drivative.1971.
117.Holy,A.,Studies on S-Adenosyl-L-Homocysteine Hydrolase.8.Preparation of Isomeric 3-Aminopropylamino Derivatives of “9-(Rs)-(2,3-Dihydroxypropyl)Adenine.Collection of Czechoslovak Chemical Communications 1983,48,(7),1910-1921.
118.Holy, A., Studies on S-Adenosyl-L-Homocysteine Hydrolase .6. Preparation of Enantiomeric and Racemic 2,3,4,5-Tetrahydroxypentyl Derivatives of Adenine,Cytosine and Uracil.Collection of Czechoslovak Chemical Communications 1982,47,(10),2786-2805.
119.Votruba,I.;Holy,A.,Inhibition of S-Adenosyl-L-Homocysteine Hydrolase by the Aliphatic Nucleoside Analog-9-(S)-(2,3-Dihydroxypropyl)Adenine.Collection of Czechoslovak Chemical Communications 1980,45,(11),3039-3044.
120.Cihak, A.; Holy, A., Distribution and Metabolic Transformation of "9-(S)-(2,3-Dihydroxypropyl)Adenine,an Effective Virostatic Agent,in Mice.Collection of Czechoslovak Chemical Communications 1978,43,(8),2082-2088.
121.Holy,A.;Sorm,F.,Nucleic Acid Components and Their Analogues.129.Synthesis of Enantiomeric 2',3'-Cyclic Phosphates of 9-(Alpha-Lyxofuranosyl)Adenine and-Hypoxanthine,and Their Behaviour Towards Ribonuclease T1 and T2.Collection of Czechoslovak Chemical Communications 1969,34,(11),3523-&.
122.Anonymous;Yuan,C.-S.Reversible inhibitors of SAH hydrolase and uses thereof.US 07196093,2007.
123.Denmark,S.E.;Yang,S.M.,Total synthesis of (+)-brasilenyne.Application of an intramolecular silicon-assisted cross-coupling reaction.Journal of the American Chemical Society 2004,126,(39),12432-12440.
124.Fkyerat,A.;Demeunynck,M.;Constant,J.F.;Michon,P.;Lhomme,J.,A New Class of Artificial Nucleases That Recognize and Cleave Apurinic Sites in DNA with Great Selectivity and Efficiency.Journal of the American Chemical Society 1993,115,(22),9952-9959.
125.Ciapetti,P.;Taddei,M.,A simple preparation of N-vinyl derivatives of DNA nucleobases.Tetrahedron 1998,54,(37),11305-11310.
126.Ali,I.;Aboul-Enein,H.Y.;Ghanem,A.,Enantioselective toxicity and carcinogenesis. Current PharmaceuticalAnalysis 2005,1,(1),109-125.
127.Lira,E.P.;Huffrnan,C.W.,Some Michael-Type Reactions with Adenine.Journal of Organic Chemistry 1966,31,(7),2188-&.
128.Burling,S.;Paine,B.M.;Nama,D.;Brown,V.S.;Mahon,M.F.;Prior,T.J.;Pregosin,P.S.;Whittlesey,M.K.;Williams,J.M.J.,C-H activation reactions of ruthenium N-heterocyclic carbene complexes:Application in a catalytic tandem reaction involving C-C bond formation from alcohols.Journal of the American Chemical Society 2007,129,(7),1987-1995.
129.Lozada-Ramirez,J.D.;Martinez-Martinez,I.;Sanchez-Ferrer,A.;Garcia-Carmona,F.,A colorimetric assay for S-adenosylhomocysteine hydrolase.Journal of Biochemical and Biophysical Methods 2006,67,(2-3),131-140.
130.Yang,X.D.;Hu,Y.B.;Yin,D.H.;Turner,M.A.;Wang,M.;Borchardt,R.T.;Howell,P.L.;Kuczera,K.;Schowen,R.L.,Catalytic strategy of S-adenosyl-L-homocysteine hydrolase:Transition-state stabilization and the avoidance of abortive reactions.Biochemistry 2003,42,(7),1900-1909.