新型靶向型苊并“1，2-b”吡咯类及萘酰亚胺类抗肿瘤剂的设计合成与生物性能
|
摘要
本论文基于苊并[1,2-b]吡咯和萘酰亚胺母体结构,设计合成了三系列新型抗肿瘤药物先导,详细研究了它们的抗肿瘤性能及作用机理,发现了它们有别于已报道的该类衍生物的全新的作用靶点,例如成纤维细胞生长因子受体(FGFR1)、溶酶体膜通透性(LMP)等。
第一系列化合物为苊并[1,2-b]吡咯衍生物。通过在苊并[1,2-b]吡咯的3位引入多种硫醇和／或9位引入各种多种酯类,设计合成了20个新结构目标化合物。10种肿瘤细胞的细胞毒性测试结果表明该系列化合物具有很强的抗肿瘤活性,IC50值为10-6—10-8M。代表性化合物2a-b酪氨酸激酶抑制活性普筛结果表明,它们对FGFR1有较强选择性。进一步研究证实该系列化合物中的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯类衍生物2a-d对FGFR1有较强抑制作用,IC50值达到0.019-0.077μM。而其烯丙基硫醇衍生物同样具有良好的的FGFR1抑制作用,IC50值在0.2-0.6μM。它们对FGFR1抑制活性与抗肿瘤活性的构效关系一致。计算机模拟分子对接表明2a-b能与FGFR1的ATP位点结合。这是苊并[1,2-b]吡咯衍生物第一次用作FGFR1抑制剂。
第二系列化合物为多靶点萘酰亚胺类抗肿瘤剂。通过在萘酰亚胺的2位和6位分别引入长烷链和多胺结构,设计合成了8个新结构目标化合物,同时设计合成了4个对照化合物。5种肿瘤细胞的细胞毒性测试结果表明该系列化合物具有较强的抗肿瘤活性,IC50值为10-5—10-6。圆二色谱、荧光广谱等实验结果表明,该系列化合物与DNA几乎没有直接作用,但是kDNA解链环实验证实在非细胞体系中该系列化合物具有一定的topoⅡ抑制活性。此外,LMP实验证实该系列化合物中的7b-d具有较好的LMP作用,这和与其它同类类似物相比表现出的抗肿瘤性能优势一致。细胞色素c释放和Annexin V-FITC双染实验证实：化合物7a-d和8a-d能高效诱导细胞通过线粒体途径凋亡。本章工作提出了一种新型多靶点药物设计思想,并进行了初步验证。
第三系列化合物为萘酰亚胺—大环多胺加合物。通过在萘酰亚胺的2-位和6-位分别引入大环多胺和不同长度的烷链,设计合成了5个目标化合物。5种肿瘤细胞的细胞毒性测试表明该系列化合物具有较强的抗肿瘤活性,IC50值为10-5—10-6M。圆二色谱和DNA解螺旋实验表明,萘酰亚胺—大环多胺加合物与DNA的直接作用比较温和,kDNA解链环实验证实在非细胞体系中萘酰亚胺—大环多胺加合物具有较强的topoⅡ抑制活性。在上述实验中我们还发现,烷链长度可以调节化合物和上述靶点的作用强度。Annexin V-FITC双染实验证实：萘酰亚胺—大环多胺加合物有较强的诱导肿瘤细胞凋亡的作用。
In the dissertation, three series of acenaphtho[1,2-b]pyrrole or naphthalimide derivatives were designed and synthesized. They were evaluated of their antitumor potency and confirmed of their mechanism of action. Comparing with their analogs reported before, several compounds were proved to possess novel molecular targets like fibroblast growth factor receptor 1 (FGFR1), lysosomal membrane permeabilization (LMP).
In the first section, the antitumor activities of acenaphtho[1,2-b]pyrrole derivatives were studied. Twenty target compounds were designed and synthesized by introduction of sulfur, nucleophiles at 3-position, and/or by esterification with bromide/iodide at the 9-position. This novel series of acenaphtho[1,2-b]pyrrole derivatives were discovered as FGFR1 inhibitors with submicormolar to double digital nanomolar IC50 values and exhibited outstanding growth inhibition property in vitro with micromolar to double digital nanomolar IC50 values. The structure-activity relationship (SAR) studies showed that acenaphtho[1,2-b]pyrrole-carboxylic acid esters (2a-d) possess distinguished FGFR1 inhibition activity, e.g. compound 2b showed IC50 values of 19 nM. The thiol derivatives of the esters (3a-h) could also be great FGFR1 inhibitors with submicromolar IC50 values which varied with 3-position substitution. Additionally, compounds 2a-b were validated for their excellent selectivity against diverse kinases, like VEGFRs and PDGFRs. The antiproliferative results were quite consistent with their FGFR1 inhibition activities, especially for compound 2a-d and 3a-h. Molecular docking simulation demonstrated that compounds 2a-b occupied the ATP-binding domain. After all, these are the first examples of FGFR1 inhibitors based on acenaphtho[1,2-b]pyrrole scaffold.
In the second section, the antitumor activities of multitarget naphthalimide derivatives were studied. Eight novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with polyamines and long alkyl chains. Besides,4 compounds were synthesized as reference. Majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC50 values ranging from 2 to 10μM and are more active than Amonafide. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topoⅡinhibitors. Furthermore, compounds 7b-d were found to notably induce LMP, and exhibited better antiproliferative activity comparing with their single-target analogs. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.
In the third section, the antitumor activities of naphthalimide-cyclam conjugates with alkyl chains were studied. Five novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with cyclam and alkyl chains. They exhibited potent growth inhibition property in vitro with the IC50 values of 1005-10-6 M. These compounds were demonstrated to be quite modest DNA binders according to circular dichroism (CD) spectra and DNA relaxation assay, but quite potent topoⅡinhibitors in cell-free system due to kDNA decatenation assay. Besides, the length of alkyl chains could be utilized to adjust the binding of the compounds towards DNA and topoⅡ. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis.
第一系列化合物为苊并[1,2-b]吡咯衍生物。通过在苊并[1,2-b]吡咯的3位引入多种硫醇和／或9位引入各种多种酯类,设计合成了20个新结构目标化合物。10种肿瘤细胞的细胞毒性测试结果表明该系列化合物具有很强的抗肿瘤活性,IC50值为10-6—10-8M。代表性化合物2a-b酪氨酸激酶抑制活性普筛结果表明,它们对FGFR1有较强选择性。进一步研究证实该系列化合物中的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯类衍生物2a-d对FGFR1有较强抑制作用,IC50值达到0.019-0.077μM。而其烯丙基硫醇衍生物同样具有良好的的FGFR1抑制作用,IC50值在0.2-0.6μM。它们对FGFR1抑制活性与抗肿瘤活性的构效关系一致。计算机模拟分子对接表明2a-b能与FGFR1的ATP位点结合。这是苊并[1,2-b]吡咯衍生物第一次用作FGFR1抑制剂。
第二系列化合物为多靶点萘酰亚胺类抗肿瘤剂。通过在萘酰亚胺的2位和6位分别引入长烷链和多胺结构,设计合成了8个新结构目标化合物,同时设计合成了4个对照化合物。5种肿瘤细胞的细胞毒性测试结果表明该系列化合物具有较强的抗肿瘤活性,IC50值为10-5—10-6。圆二色谱、荧光广谱等实验结果表明,该系列化合物与DNA几乎没有直接作用,但是kDNA解链环实验证实在非细胞体系中该系列化合物具有一定的topoⅡ抑制活性。此外,LMP实验证实该系列化合物中的7b-d具有较好的LMP作用,这和与其它同类类似物相比表现出的抗肿瘤性能优势一致。细胞色素c释放和Annexin V-FITC双染实验证实：化合物7a-d和8a-d能高效诱导细胞通过线粒体途径凋亡。本章工作提出了一种新型多靶点药物设计思想,并进行了初步验证。
第三系列化合物为萘酰亚胺—大环多胺加合物。通过在萘酰亚胺的2-位和6-位分别引入大环多胺和不同长度的烷链,设计合成了5个目标化合物。5种肿瘤细胞的细胞毒性测试表明该系列化合物具有较强的抗肿瘤活性,IC50值为10-5—10-6M。圆二色谱和DNA解螺旋实验表明,萘酰亚胺—大环多胺加合物与DNA的直接作用比较温和,kDNA解链环实验证实在非细胞体系中萘酰亚胺—大环多胺加合物具有较强的topoⅡ抑制活性。在上述实验中我们还发现,烷链长度可以调节化合物和上述靶点的作用强度。Annexin V-FITC双染实验证实：萘酰亚胺—大环多胺加合物有较强的诱导肿瘤细胞凋亡的作用。
In the dissertation, three series of acenaphtho[1,2-b]pyrrole or naphthalimide derivatives were designed and synthesized. They were evaluated of their antitumor potency and confirmed of their mechanism of action. Comparing with their analogs reported before, several compounds were proved to possess novel molecular targets like fibroblast growth factor receptor 1 (FGFR1), lysosomal membrane permeabilization (LMP).
In the first section, the antitumor activities of acenaphtho[1,2-b]pyrrole derivatives were studied. Twenty target compounds were designed and synthesized by introduction of sulfur, nucleophiles at 3-position, and/or by esterification with bromide/iodide at the 9-position. This novel series of acenaphtho[1,2-b]pyrrole derivatives were discovered as FGFR1 inhibitors with submicormolar to double digital nanomolar IC50 values and exhibited outstanding growth inhibition property in vitro with micromolar to double digital nanomolar IC50 values. The structure-activity relationship (SAR) studies showed that acenaphtho[1,2-b]pyrrole-carboxylic acid esters (2a-d) possess distinguished FGFR1 inhibition activity, e.g. compound 2b showed IC50 values of 19 nM. The thiol derivatives of the esters (3a-h) could also be great FGFR1 inhibitors with submicromolar IC50 values which varied with 3-position substitution. Additionally, compounds 2a-b were validated for their excellent selectivity against diverse kinases, like VEGFRs and PDGFRs. The antiproliferative results were quite consistent with their FGFR1 inhibition activities, especially for compound 2a-d and 3a-h. Molecular docking simulation demonstrated that compounds 2a-b occupied the ATP-binding domain. After all, these are the first examples of FGFR1 inhibitors based on acenaphtho[1,2-b]pyrrole scaffold.
In the second section, the antitumor activities of multitarget naphthalimide derivatives were studied. Eight novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with polyamines and long alkyl chains. Besides,4 compounds were synthesized as reference. Majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC50 values ranging from 2 to 10μM and are more active than Amonafide. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topoⅡinhibitors. Furthermore, compounds 7b-d were found to notably induce LMP, and exhibited better antiproliferative activity comparing with their single-target analogs. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.
In the third section, the antitumor activities of naphthalimide-cyclam conjugates with alkyl chains were studied. Five novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with cyclam and alkyl chains. They exhibited potent growth inhibition property in vitro with the IC50 values of 1005-10-6 M. These compounds were demonstrated to be quite modest DNA binders according to circular dichroism (CD) spectra and DNA relaxation assay, but quite potent topoⅡinhibitors in cell-free system due to kDNA decatenation assay. Besides, the length of alkyl chains could be utilized to adjust the binding of the compounds towards DNA and topoⅡ. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis.
引文
1.甄永苏,抗肿瘤药物研究与开发.北京：化学工业出版社2004,9.
2. Thurston, D. E.;刘吉成译,Chemistry and Pharmacology of Anticancer Drugs (抗肿瘤药物的化学和药理学)北京：人民卫生出版社2008,9.
3.郭青龙,肿瘤药理学.北京：化学工业出版社2007,12.
4.胥彬,肿瘤药理学新论.北京：人民闻声出版社2004,5.
5. Hanahan, D.; Weinberg, R. A., The hallmarks of cancer. Cell 2000,100(1):57-70.
6. Ullrich, A., Tyrosine kinases as targets for cancer therapy. Clin. Cancer Res.2001,7(11): 3815s-3815s.
7. Levitzki, A.; Gazit, A., Tyrosine kinase inhibition:an approach to drug development. Science 1995,267(5205):1782-1788.
8. Baselga, J., Targeting tyrosine kinases in cancer:The second wave. Science 2006, 312(5777):1175-1178.
9. Cohen, P., Protein kinases--the major drug targets of the twenty-first century? Nat. Rev. Drug Discov.2002,1(4):309-315.
10. Schlessinger, J., Cell signaling by receptor tyrosine kinases. Cell 2000,103(2):211-225.
11. Noble, M. E. M.; Endicott, J. A.; Johnson, L. N., Protein kinase inhibitors:Insights into drug design from structure. Science 2004,303(5665):1800-1805.
12. Gschwind, A.; Fischer, O. M.; Ullrich, A., Timeline-The discovery of receptor tyrosine kinases:targets for cancer therapy. Nat. Rev. Cancer 2004,4(5):361-370.
13. Gschwind, A.; Fischer, O. M.; Ullrich, A., Receptor tyrosine kinases as targets for cancer therapy development. Insights into Receptor Function and New Drug Development Targets 2006:167-178.
14. Manetti, F.; Botta, M, Small-molecule inhibitors of fibroblast growth factor receptor (FGFR) tyrosine kinases (TK). Curr. Pharm. Des.2003,9(7):567-581.
15. Yarden, Y.; Sliwkowski, M. X., Untangling the ErbB signalling network. Nature Reviews Molecular Cell Biology 2001,2(2):127-137.
16. Antonello, A.; Tarozzi, A.; Morroni, F.; Cavalli, A.; Rosini, M.; Hrelia, P.; Bolognesi, M. L.; Melchiorre, C, Multitarget-directed drug design strategy:A novel molecule designed to block epidermal growth factor receptor (EGFR) and to exert proapoptotic effects. J Med Chem 2006,49(23):6642-6645.
17. Min, J. K.; Han, K. Y.; Kim, E. C.; Kim, Y. M.; Lee, S. W.; Kim, O. H.; Kim, K. W.; Gho, Y. S.; Kwon, Y. G., Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res.2004, 64(2):644-651.
18. Kim, K. J.; Li, B.; Winer, J.; Armanini, M.; Gillett, N.; Phillips, H. S.; Ferrara, N., Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993,362(6423):841-844.
19. Mohammadi, M.; McMahon, G; Sun, L.; Tang, C.; Hirth, P.; Yeh, B. K.; Hubbard, S. R.; Schlessinger, J., Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 1997,276(5314):955-960.
20. Knights, V.; Cook, S. J., De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol. Then 2010,125(1):105-117.
21. Thompson, A. M; Connolly, C. J. C; Hamby, J. M.; Boushelle, S.; Hartl, B. G; Amar, A. M.; Kraker, A. J.; Driscoll, D. L.; Steinkampf, R. W.; Patmore, S. J.; Vincent, P. W.; Roberts, B. J.; Elliott, W. L.; Klohs, W.; Leopold, W. R.; Showalter, H. D. H.; Denny, W. A., 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and related 2-urea derivatives are potent and selective inhibitors of the FGF receptor-1 tyrosine kinase. J. Med. Chem.2000, 43(22):4200-4211.
22. Lokker, N. A.; Sullivan, C. M.; Hollenbach, S. J.; Israel, M. A.; Giese, N. A., Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells:Evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res.2002,62(13):3729-3735.
23. Levin, M.; D'Souza, N.; Castaner, J., Iressa (TM). Oncolytic, EGF receptor tyrosine kinase inhibitor. Drugs of the Future 2002,27(4):339-345.
24. Konecny, G. E.; Venkatesan, N.; Yang, G.; Dering, J.; Ginther, C.; Finn, R.; Rahmeh, M.; Fejzo, M. S.; Toft, D.; Jiang, S. W.; Slamon, D. J.; Podratz, K. C, Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells. Br. J. Cancer 2008, 98(6):1076-1084.
25. Erlichman, C; Hidalgo, M.; Boni, J. P.; Martins, P.; Quinn, S. E.; Zacharchuk, C.; Amorusi, P.; Adjei, A. A.; Rowinsky, E. K., Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J. Clin. Oncol.2006,24(15):2252-2260.
26. Rabindran, S. K.; Discafani, C. M.; Rosfjord, E. C.; Baxter, M.; Floyd, M. B.; Golas, J.; Hallett, W. A.; Johnson, B. D.; Nilakantan, R.; Overbeek, E.; Reich, M. F.; Shen, R.; Shi, X. Q.; Tsou, H. R.; Wang, Y. F.; Wissner, A., Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res.2004,64(11):3958-3965.
27. Golas, J. M.; Arndt, K.; Etienne, C; Lucas, J.; Nardin, D.; Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D. H.; Boschelli, F., SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res.2003, 63(2):375-381.
28. Laird, A. D.; Vajkoczy, P.; Shawver, L. K.; Thurnher, A.; Liang, C.; Mohammadi, M.; Schlessinger, J.; Ullrich, A.; Hubbard, S. R.; Blake, R. A.; Fong, T. A. T.; Strawn, L. M.; Sun, L.; Tang, C.; Hawtin, R.; Tang, F.; Shenoy, N.; Hirth, K. P.; McMahon, G.; Cherrington, J. M., SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res.2000,60(15):4152-4160.
29. Motzer, R. J.; Rini, B. I.; Bukowski, R. M.; Curti, B. D.; George, D. J.; Hudes, G R.; Redman, B. G.; Margolin, K. A.; Merchan, J. R.; Wilding, G.; Ginsberg, M. S.; Bacik, J.; Kim, S. T.; Baum, C. M.; Michaelson, M. D., Sunitinib in patients with metastatic renal cell carcinoma. Jama-Journal of the American Medical Association 2006,295(21):2516-2524.
30. Weisberg, E.; Manley, P. W.; Cowan-Jacob, S. W.; Hochhaus, A.; Griffin, J. D., Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat. Rev. Cancer 2007,7(5):345-356.
31. Hochhaus, A.; Kantarjian, H. M.; Baccarani, M.; Lipton, J. H.; Apperley, J. F.; Druker, B. J.; Facon, T.; Goldberg, S. L.; Cervantes, F.; Niederwieser, D.; Silver, R. T.; Stone, R. M.; Hughes, T. P.; Muller, M. C.; Ezzeddine, R.; Countouriotis, A. M.; Shah, N. P., Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007,109(6):2303-2309.
32. Yokoi, K.; Thaker, P. H.; Yazici, S.; Rebhun, R. R.; Nam, D. H.; He, J. Q.; Kim, S. J.; Abbruzzese, J. L.; Hamilton, S. R.; Fidler, I. J., Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res.2005,65(9):3716-3725.
33. Traxler, P.; Allegrini, P. R.; Brandt, R.; Brueggen, J.; Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.; McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wartmann, M.; Wood, J.; Caravatti, G., AEE788:A dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res.2004,64(14):4931-4941.
34. Rixe, O.; Bukowski, R. M.; Michaelson, M. D.; Wilding, G.; Hudes, G R.; Bolte, O.; Motzer, R. J.; Bycott, P.; Liou, K. F.; Freddo, J.; Trask, P. C.; Kim, S.; Rini, B. I., Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer:a phase Ⅱ study. Lancet Oncology 2007,8(11):975-984.
35. Sonpavde, G; Hutson, T. E., Pazopanib:a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 2007,9(2):115-119.
36. Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S., Discovery and development of sorafenib:a multikinase inhibitor for treating cancer. Nature Reviews Drug Discovery 2006,5(10):835-844.
37. Beebe, J. S.; Jani, J. P.; Knauth, E.; Goodwin, P.; Higdon, C.; Rossi, A. M.; Emerson, E.; Finkelstein, M.; Floyd, E.; Harriman, S.; Atherton, J.; Hillerman, S.; Soderstrom, C.; Kou, K.; Gant, T.; Noe, M. C.; Foster, B.; Rastinejad, F.; Marx, M. A.; Schaeffer, T.; Whalen, P. M.; Roberts, W. G., Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res.2003, 63(21):7301-7309.
38. Hurley, L. H., DNA and its associated processes as targets for cancer therapy. Nat. Rev. Cancer 2002,2(3):188-200.
39. Brana, M. F.; Cacho, M.; Gradillas, A.; de Pascual-Teresa, B.; Ramos, A., Intercalators as anticancer drugs. Curr. Pharm. Des.2001,7(17):1745-1780.
40.吴爱斌,新颖萘酰亚胺类抗肿瘤剂的设计合成与生物性能：(博士学位论文).上海：华东理工大学2009.
41.殷红,新型萘酰亚胺类抗肿瘤药物先导的设计、合成及构效关系研究：(博士学位论文).上海：华东理工大学2006.
42. Krapcho, A. P.; Getahun, Z.; Avery, K. L.; Vargas, K. J.; Hacker, M. P.; Spinelli, S.; Pezzoni, G.; Manzotti, C, Synthesis and antitumor evaluations of symmetrically and unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones and 1,4-bis[(aminoalkyl)amino]-5,8-dihydroxyanthracene-9,10-diones. J. Med. Chem.1991,34(8): 2373-2380.
43. Xiao, Y.; Liu, F.; Qian, X.; Cui, J., A new class of long-wavelength fluorophores:strong red fluorescence, convenient synthesis and easy derivation. Chem. Commun.2005, (2): 239-241.
44. Zhang, Z.; Yang, Y.; Zhang, D.; Wang, Y.; Qian, X.; Liu, F., Acenaphtho[1,2-b]pyrrole derivatives as new family of intercalators:Various DNA binding geometry and interesting antitumor capacity. Bioorg. Med. Chem.2006,14(20):6962-6970.
45. Brana, M. F.; Ramos, A., Naphthalimides as anti-cancer agents:Synthesis and biological activity. Curr. Med. Chem.:Anti-Cancer Agents 2001,1(3):237-255.
46. Sami, S. M.; Dorr, R. T.; Solyom, A. M.; Alberts, D. S.; Remers, W. A., Amino-Substituted 2-[2-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. Synthesis, Antitumor Activity, and Quantitative Structure-Activity Relationship. J. Med. Chem.1995,38(6):983-993.
47. Sami, S. M.; Dorr, R. T.; Alberts, D. S.; Remers, W. A.,2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent. J. Med. Chem.1993,36(6):765-770.
48. Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.; Ribaucour, F.; Simon, G.; Sauvage, S.; Gaussin, J. F.; Tuti, J.; El Yazidi, M.; Van Vynckt, F.; Mijatovic, T.; Lefranc, R; Darro, F.; Kiss, R.,2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin5-yl} carbamoyl) acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity. J. Med. Chem.2007,50(17): 4122-4134.
49. Bousquet, P. F.; Brana, M. F.; Conlon, D.; Fitzgerald, K. M.; Perron, D.; Cocchiaro, C.; Miller, R.; Moran, M.; George, J.; Qian, X. D., Preclinical evaluation of LU 79553:a novel bis-naphthalimide with potent antitumor activity. Cancer Res.1995,55(5):1176-1180.
50. McRipley, R. J.; Burns-Horwitz, P. E.; Czerniak, P. M.; Diamond, R. J.; Diamond, M. A.; Miller, J. L.; Page, R. J.; Dexter, D. L.; Chen, S. F.; Sun, J. H., Efficacy of DMP 840:a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity. Cancer Res. 1994,54(1):159-164.
51. Qian, X. H.; Li, Z. G.; Yang, Q., Highly efficient antitumor agents of heterocycles containing sulfur atom:Linear and angular thiazonaphthalimides against human lung cancer cell in vitro. Biorg. Med. Chem.2007,15(21):6846-6851.
52. Li, F.; Cui, J. N.; Guo, L. Y.; Qian, X. H.; Ren, W. M.; Wang, K. W.; Liu, F.Y, Molecular design, chemical synthesis, and biological evaluation of'4-1'pentacyclic aryl/heteroaryl-imidazonaphthalimides. Biorg. Med. Chem.2007,15(15):5114-5121.
53. Li, Y. G.; Xu, Y. F.; Qian, X. H.; Qu, B., Naphthalimide-thiazoles as novel photonucleases: molecular design, synthesis, and evaluation. Tetrahedron Lett.2004,45(6):1247-1251.
54. Li, Z. G.; Yang, Q.; Qian, X. H., Synthesis, antitumor and DNA photocleaving activities of novel naphthalene carboxamides:effects of different thio-heterocyclic rings and aminoalkyl side chains. Tetrahedron 2005,61(36):8711-8717.
55. Li, Z. G.; Yang, Q.; Qian, X. H., Novel thiazonaphthalimides as efficient antitumor and DNA photocleaving agents:Effects of intercalation, side chains, and substituent groups. Biorg. Med. Chem.2005,13(16):4864-4870.
56. Ott, I.; Xu, Y. F.; Liu, J. W.; Kokoschka, M.; Harlos, M.; Sheldrick, W. S.; Qian, X. H., Sulfur-substituted naphthalimides as photoactivatable anticancer agents:DNA interaction, fluorescence imaging, and phototoxic effects in cultured tumor cells. Biorg. Med. Chem.2008, 16(15):7107-7116.
57. Wu, A. B.; Xu, Y. F.; Qian, X. H., Novel naphthalimide-amino acid conjugates with flexible leucine moiety as side chain:Design, synthesis and potential antitumor activity. Biorg. Med. Chem.2009,17(2):592-599.
58. Wu, A. B.; Xu, Y. F.; Qian, X. H.; Wang, J.; Liu, J. W., Novel naphthalimide derivatives as potential apoptosis-inducing agents:Design, synthesis and biological evaluation. Eur. J. Med. Chem.2009,44(11):4674-4680.
59. Yang, Q.; Yang, P.; Qian, X. H.; Tong, L. P., Naphthalimide intercalators with chiral amino side chains:Effects of chirality on DNA binding, photodamage and antitumor cytotoxicity. Bioorg. Med. Chem. Lett.2008,18(23):6210-6213.
60. Zhang, W.; Qian, X. H.; Wu, Y. L.; Ohrui, H., A new class of DNA intercalator and photocleaver:Bis-naphthailimides with bromo and nitro substituents. Heterocycl. Commun. 2003,9(3):229-234.
61. Zhu, H.; Huang, M; Yang, F.; Chen, Y; Miao, Z. H.; Qian, X. H.; Xu, Y. F.; Qin, Y. X.; Luo, H. B.; Shen, X.; Geng, M. Y; Cai, Y J.; Ding, J., R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase Ⅱ. Mol. Cancer Then 2007, 6(2):484-495.
62. Hurley, L. H., DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer 2002,2(3):188-200.
63. Moore, M. J. B.; Schultes, C. M.; Cuesta, J.; Cuenca, F.; Gunaratnam, M.; Tanious, F.A.; Wilson, W. D.; Neidle, S., Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6-and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation. J. Med. Chem.2006,49(2):582-599.
64. Leonetti, C.; Scarsella, M.; Riggio, G.; Rizzo, A.; Salvati, E.; D'Incalci, M.; Staszewsky, L.; Frapolli, R.; Stevens, M. F.; Stoppacciaro, A.; Mottolese, M.; Antoniani, B.; Gilson, E.; Zupi, G.; Biroccio, A., G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors. Clin. Cancer Res.2008,14(22): 7284-7291.
65. Zhou, J. L.; Lu, Y. J.; Ou, T. M.; Zhou, J. M.; Huang, Z. S.; Zhu, X. R.; Du, C. J.; Bu, X. Z.; Ma, L.; Gu, L. Q.; Li, Y M.; Chan, A. S. C, Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase. J. Med. Chem.2005,48(23):7315-7321.
66. Huang, J.; Li, G. R.; Wu, Z. G.; Song, Z. B.; Zhou, Y.Y.; Shuai, L.; Weng, X. C; Zhou, X.; Yang, G. F., Bisbenzimidazole to benzobisimidazole:from binding B-form duplex DNA to recognizing different modes of telomere G-quadruplex. Chem. Commun.2009, (8):902-904.
67. Seenisamy, J.; Bashyam, S.; Gokhale, V.; Vankayalapati, H.; Sun, D.; Siddiqui-Jain, A.; Streiner, N.; Shin-ya, K.; White, E.; Wilson, W. D.; Hurley, L. H., Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J. Am. Chem. Soc.2005,127(9):2944-2959.
68. De Cian, A.; DeLemos, E.; Mergny, J. L.; Teulade-Fichou, M. P.; Monchaud, D., Highly efficient G-quadruplex recognition by bisquinolinium compounds. J. Am. Chem. Soc.2007, 129(7):1856-1857.
69. Sun, D.; Thompson, B.; Cathers, B. E.; Salazar, M.; Kerwin, S. M.; Trent, J. O.; Jenkins, T. C.; Neidle, S.; Hurley, L. H., Inhibition of human telomerase by a G-quadruplex-interactive compound. J. Med. Chem.1997,40(14):2113-2116.
70. Anantha, N. V.; Azam, M.; Sheardy, R. D., Porphyrin Binding to Quadruplexed T4G4. Biochemistry (Mosc).1998,37(9):2709-2714.
71. Wheelhouse, R. T.; Sun, D.; Han, H.; Han, F. X.; Hurley, L. H., Cationic Porphyrins as Telomerase Inhibitors:the Interaction of Tetra-(N-methyl-4-pyridyl)porphine with Quadruplex DNA. J. Am. Chem. Soc.1998,120(13):3261-3262.
72. Kim, M. Y.; Gleason-Guzman, M.; Izbicka, E.; Nishioka, D.; Hurley, L. H., The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures. Cancer Res.2003, 63(12):3247-3256.
73. Fedoroff, O. Y.; Salazar, M.; Han, H.; Chemeris, V. V.; Kerwin, S. M.; Hurley, L. H., NMR-Based Model of a Telomerase-Inhibiting Compound Bound to G-Quadruplex DNAf. Biochemistry (Mosc).1998,37(36):12367-12374.
74. Han, H.; Cliff, C. L.; Hurley, L. H., Accelerated Assembly of G-Quadruplex Structures by a Small Moleculet. Biochemistry (Mosc).1999,38(22):6981-6986.
75. Kern, J. T.; Thomas, P. W.; Kerwin, S. M., The relationship between ligand aggregation and G-quadruplex DNA selectivity in a series of 3,4,9,10-perylenetetracarboxylic acid diimides. Biochemistry (Mosc).2002,41(38):11379-11389.
76. Guo, Q.; Lu, M.; Marky, L. A.; Kallenbach, N. R., Interaction of the dye ethidium bromide with DNA containing guanine repeats. Biochemistry (Mosc).1992,31(9): 2451-2455.
77. Teulade-Fichou, M. P.; Carrasco, C; Guittat, L.; Bailly, C; Alberti, P.; Mergny, J. L.; David, A.; Lehn, J. M.; Wilson, W. D., Selective recognition of G-quadruplex telomeric DNA by a bis(quinacridine) macrocycle. .. Am. Chem. Soc.2003,125(16):4732-4740.
78. Liu, W.; Bulgaru, A.; Haigentz, M.; Stein, C. A.; Perez-Soler, R.; Mani, S., The BCL2-family of protein ligands as cancer drugs:the next generation of therapeutics. Curr Med Chem Anticancer Agents 2003,3(3):217-223.
79. Manion, M. K.; Fry, J.; Schwartz, P. S.; Hockenbery, D. M, Small-molecule inhibitors of Bcl-2. Current opinion in investigational drugs (London, England:2000) 2006,7(12): 1077-1084.
80. Doshi, J. M; Tian, D. F.; Xing, C. G, Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA 14-1), an antagonist for antiapoptotic Bcl-2 proteins to overcome drug resistance in cancer. J. Med. Chem.2006,49(26):7731-7739.
81. Chan, S. L.; Lee, M. C; Tan, K. O.; Yang, L. K.; Lee, A. S. Y.; Flotow, H.; Fu, N. Y; Butler, M. S.; Soejarto, D. D.; Buss, A. D.; Yu, V. C., Identification of chelerythrine as an inhibitor of BclXL function. J. Biol. Chem.2003,278(23):20453-20456.
82. Degterev, A.; Lugovskoy, A.; Cardone, M; Mulley, B.; Wagner, G.; Mitchison, T.; Yuan, J. Y, Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-x(L). Nat. Cell Biol.2001,3(2):173-182.
83. Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong, R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.; Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.; Kunzer, A. R.; Letai, A.; Li, C; Mitten, M. J.; Nettesheim, D. G.; Ng, S.; Nimmer, P. M.; O'Connor, J. M.; Oleksijew, A.; Petros, A. M.; Reed, J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.; Wang, B. L.; Wendt, M. D.; Zhang, H. C; Fesik, S. W.; Rosenberg, S. H., An inhibitor of Bel-2 family proteins induces regression of solid tumours. Nature 2005,435(7042):677-681.
84. van Delft, M. R.; Wei, A. H.; Mason, K. D.; Vandenberg, C. J.; Chen, L.; Czabotar, P. E.; Willis, S. N.; Scott, C. L.; Day, C. L.; Cory, S.; Adams, J. M.; Roberts, A. W.; Huang, D. C. S., The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006,10(5):389-399.
85. Wang, Y.; Serradell, N.; Bolos, J.; Rosa, E., Obatoclax mesilate-Bcl-2 inhibitor, apoptosis inducer, oncolytic. Drugs of the Future 2007,32(3):228-233.
86. Tang, G. Z.; Nikolovska-Coleska, Z.; Qiu, S.; Yang, C. Y.; Guo, J.; Wang, S. M., Acylpyrogallols as inhibitors of antiapoptotic Bcl-2 proteins. J. Med. Chem.2008,51(4): 717-720.
87. Zhang, Z.; Jin, L.; Qian, X.; Wei, M.; Wang, Y.; Wang, J.; Yang, Y.; Xu, Q.; Xu, Y; Liu, F., Novel Bcl-2 inhibitors:discovery and mechanism study of small organic apoptosis-inducing agents. ChemBioChem 2007,8(1):113-121.
88. Boya, P.; Andreau, K.; Poncet, D.; Zamzami, N.; Perfettini, J. L.; Metivier, D.; Ojcius, D. M.; Jaattela, M.; Kroemer, G, Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J. Exp. Med.2003,197(10):1323-1334.
89. Boya, P.; Kroemer, G, Lysosomal membrane permeabilization in cell death. Oncogene 2008,27(50):6434-6451.
90. Kagedal, K.; Zhao, M.; Svensson, I.; Brunk, U. T., Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem. J2001,359:335-343.
91. Ostenfeld, M. S.; Fehrenbacher, N.; Hoyer-Hansen, M.; Thomsen, C.; Farkas, T.; Jaattela, M., Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res.2005,65(19):8975-8983.
92. Boya, P.; Gonzalez-Polo, R. A.; Poncet, D.; Andreau, K.; Vieira, H. L. A.; Roumier, T.; Perfettini, J. L.; Kroemer, G, Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003,22(25): 3927-3936.
93. Uchimoto, T.; Nohara, H.; Kamehara, R.; Iwamura, M.; Watanabe, N.; Kobayashi, Y., Mechanism of apoptosis induced by a lysosomotropic agent, L-Leucyl-L-leucine methyl ester. Apoptosis 1999,4(5):357-362.
94. Li, W.; Yuan, X. M.; Nordgren, G; Dalen, H.; Dubowchik, G. M; Firestone, R. A.; Brunk, U. T., Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett.2000, 470(1):35-39.
95. Yu, Z. Q.; Wei, L.; Brunk, U. T.,3-aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes. APMIS 2003,111(6):643-652.
96. Sawyers, C., Targeted cancer therapy. Nature 2004,432(7015):294-297.
97. Arora, A.; Scholar, E. M., Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther.2005,315(3):971-979.
98. Zwick, E.; Bange, J.; Ullrich, A., Receptor tyrosine kinases as targets for anticancer drugs. Trends Mol. Med.2002,8(1):17-23.
99. Traxler, P.; Bold, G.; Buchdunger, E.; Caravatti, G.; Furet, P.; Manley, P.; O'Reilly, T. Wood, J.; Zimmermann, J., Tyrosine kinase inhibitors:From rational design to clinical trials. Med. Res. Rev.2001,21(6):499-512.
100. Zhang, J. M.; Yang, P. L.; Gray, N. S., Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 2009,9(1):28-39.
101. Borzilleri, R. M.; Zheng, X. P.; Qian, L. G.; Ellis, C.; Cai, Z. W.; Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R.; Kukral, D. W.; Fura, A.; Kamath, A.; Vyas, V.; Tokarski, J. S.; Barrish, J. C.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. S., Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f] [1,2,4] triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. J. Med. Chem.2005,48(12):3991-4008.
102. Gu, X.; Wang, Y.; Kumar, A.; Ye, G.; Parang, K.; Sun, G, Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase. J. Med. Chem.2006,49(25):7532-7539.
103. Tao, Z. F.; Hasvold, L. A.; Leverson, J. D.; Han, E. K.; Guan, R.; Johnson, E. F.; Stoll, V. S.; Stewart, K. D.; Stamper, G.; Soni, N.; Bouska, J. J.; Luo, Y.; Sowin, T. J.; Lin, N. H.; Giranda, V. S.; Rosenberg, S. H.; Penning, T. D., Discovery of 3H-benzo[4,5]thieno[3,2-d] pyrimidin-4-ones as potent, highly selective, and orally bioavailable inhibitors of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM) kinases. J. Med. Chem.2009,52(21):6621-6636.
104. Frey, R. R.; Curtin, M. L.; Albert, D. H.; Glaser, K. B.; Pease, L. J.; Soni, N. B.; Bouska, J. J.; Reuter, D.; Stewart, K. D.; Marcotte, P.; Bukofzer, G.; Li, J.; Davidsen, S. K.; Michaelides, M. R.,7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors. J. Med. Chem.2008,51(13):3777-3787.
105. Fabbro, D.; Manley, P. W., Su-6668. SUGEN. Curr. Opin. Investig. Drugs 2001,2(8): 1142-1148.
106. Marek, L.; Ware, K. E.; Fritzsche, A.; Hercule, P.; Helton, W. R.; Smith, J. E.; McDermott, L. A.; Coldren, C. D.; Nemenoff, R. A.; Merrick, D. T.; Helfrich, B. A.; Bunn, P. A.; Heasley, L. E., Fibroblast Growth Factor (FGF) and FGF Receptor-Mediated Autocrine Signaling in Non-Small-Cell Lung Cancer Cells. Mol. Pharmacol.2009,75(1):196-207.
107. Coskun, A.; Deniz Yilmaz, M.; Akkaya, E. U., An acenaphthopyrrolone-dipicolylamine derivative as a selective and sensitive chemosensor for group IIB cations. Tetrahedron Lett. 2006,47(22):3689-3691.
108. Zhang, M.; Yu, M.; Li, F.; Zhu, M.; Li, M.; Gao, Y.; Li, L.; Liu, Z.; Zhang, J.; Zhang, D.; Yi, T.; Huang, C, A Highly Selective Fluorescence Turn-on Sensor for Cysteine/Homocysteine and Its Application in Bioimaging. J. Am. Chem. Soc.2007,129(34): 10322-10323.
109. Liu, Y.; Xu, Y.; Qian, X.; Xiao, Y.; Liu, J.; Shen, L.; Li, J.; Zhang, Y, Synthesis and evaluation of novel 8-oxo-8H-cyclopenta[a]acenaphthylene-7-carbonitriles as long-wavelength fluorescent markers for hypoxic cells in solid tumor. Bioorg. Med. Chem. Lett.2006,16(6):1562-1566.
110. Xiong, L.; Yu, M.; Cheng, M.; Zhang, M.; Zhang, X.; Xu, C.; Li, F., A photostable fluorescent probe for targeted imaging of tumor cells possessing integrin alpha vbeta 3**. Mol. BioSyst.2009,5(3):241-243.
111. Liu, F.; Xiao, Y.; Qian, X.; Zhang, Z.; Cui, J.; Cui, D.; Zhang, R., Versatile acenaphtho[1,2-b]pyrrole-carbonitriles as a new family of heterocycles:diverse SNArH reactions, cytotoxicity and spectral behavior. Tetrahedron 2005,61(47):11264-11269.
112. Liu, F.; Qian, X.; Cui, J.; Xiao, Y.; Zhang, R.; Li, G, Design, synthesis, and antitumor evaluation of novel acenaphtho[1,2-b]pyrrole-carboxylic acid esters with amino chain substitution. Bioorg. Med. Chem.2006,14(13):4639-4644.
113. Wu, X. J.; Kassie, F.; Mersch-Sundermann, V., Induction of apoptosis in tumor cells by naturally occurring sulfur-containing compounds. Mutat. Res.-Rev. Mut. Res.2005,589(2): 81-102.
114. Aggarwal, B. B.; Shishodia, S., Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol.2006,71(10):1397-1421.
115. Isanbor, C.; O'Hagan, D., Fluorine in medicinal chemistry:A review of anti-cancer agents. J. Fluorine Chem.2006,127(3):303-319.
116. Hagmann, W. K., The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008,51(15):4359-4369.
117. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V., Fluorine in medicinal chemistry. Chem. Soc. Rev.2008,37(2):320-330.
118. Bohm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M., Fluorine in medicinal chemistry. ChemBioChem 2004,5(5):637-643.
119.刘凤玉,新苊并杂环发色团及其衍生物的合成、光谱及其作为DNA靶向分子的研究：(博士学位论文).大连：大连理工大学2006.
120. Petrelli, A.; Giordano, S., From single-to multi-target drugs in cancer therapy:When aspecificity becomes an advantage. Curr. Med. Chem.2008,15(5):422-432.
121. Fu, Z.; Malureanu, L.; Huang, J.; Wang, W.; Li, H.; Van Deursen, J. M.; Tindall, D. J.; Chen, J., Plkl-dependent phosphorylation of FoxMl regulates a transcriptional programme required for mitotic progression. Nat. Cell Biol 2008,10(9):1076-1082.
122. Overington, J. P.; Al-Lazikani, B.; Hopkins, A. L., Opinion-How many drug targets are there? Nat. Rev. Drug Discov.2006,5(12):993-996.
123. Szuromi, P.; Vinson, V.; Marshall, E., Rethinking drug discovery-Introduction. Science 2004,303(5665):1795-1795.
124. Osterborg, A.; Mellstedt, H.; Keating, M., Clinical effects of alemtuzumab (Campath-1H) in B-cell chronic lymphocytic leukemia. Med. Oncol.2002,19:S21-S26.
125. Bode, A. M.; Dong, Z. G, Cancer prevention research-then and now. Nat. Rev. Cancer 2009,9(7):508-516.
126. Zhan, P.; Liu, X. Y., Designed multiple ligands:an emerging anti-HIV drug discovery paradigm. Curr. Pharm. Des.2009,15(16):1893-1917.
127. Van der Schyf, C. J.; Geldenhuys, W. J., Polycyclic compounds:ideal drug scaffolds for the design of multiple mechanism drugs? Neurotherapeutics 2009,6(1):175-186.
128. Futerman, A. H.; Sussman, J. L.; Horowitz, M.; Silman, I.; Zimran, A., New directions in the treatment of Gaucher disease. Trends Pharmacol. Sci.2004,25(3):147-151.
129. Schrattenholz, A.; Soskic, V, What does systems biology mean for drug development? Curr. Med. Chem.2008,15(15):1520-1528.
130. Borisy, A. A.; Elliott, P. J.; Hurst, N. W.; Lee, M. S.; Lehar, J.; Price, E. R.; Serbedzija, G; Zimmermann, G. R.; Foley, M. A.; Stockwell, B. R.; Keith, C. T., Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. U. S. A.2003,100(13):7977-7982.
131. Zimmermann, G. R.; Lehar, J.; Keith, C. T., Multi-target therapeutics:when the whole is greater than the sum of the parts. Drug Discov. Today 2007,12(1-2):34-42.
132. Van der Greef, J.; McBurney, R. N., Innovation-Rescuing drug discovery:in vivo systems pathology and systems pharmacology. Nat. Rev. Drug Discov.2005,4(12):961-967.
133. Morphy, R.; Rankovic, Z., Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem.2005,48(21):6523-6543.
134. Wei, D. G.; Jiang, X. L.; Zhou, L.; Chen, J.; Chen, Z.; He, C.; Yang, K.; Liu, Y.; Pei, J. R.; Lai, L. H., Discovery of Multitarget Inhibitors by Combining Molecular Docking with Common Pharmacophore Matching. J. Med. Chem.2008,51(24):7882-7888.
135. Hopkins, A. L., Network pharmacology:the next paradigm in drug discovery. Nat. Chem. Biol.2008,4(11):682-690.
136. Kerr, J. F. R.; Wyllie, A. H.; Currie, A. R., Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972,26(4):239-257.
137. Fischer, U.; Janssen, K.; Schulze-Osthoff, K., Cutting-edge apoptosis-based therapeutics-A panacea for cancer? Biodrugs 2007,21(5):273-297.
138. Thompson, C. B., Apoptosis in the pathogenesis and treatment of disease. Science 1995, 267(5203):1456-1462.
139. Reed, J. C., Apoptosis-based therapies. Nat. Rev. Drug Discoo.2002,1(2):111-121.
140. Kroemer, G.; Galluzzi, L.; Brenner, C., Mitochondrial membrane permeabilization in cell death. Physiol. Rev.2007,87(1):99-163.
141. Tian, Z. Y.; Xie, S. Q.; Du, Y. W.; Ma, Y F.; Zhao, J.; Gao, W. Y.; Wang, C. J., Synthesis, cytotoxicity and apoptosis of naphthalimide polyamine conjugates as antitumor agents. Eur. J. Med. Chem.2009,44(1):393-399.
142. Okada, H.; Mak, T. W., Pathways of apoptotic and non-apoptotic death in tumour cells. Nat. Rev. Cancer 2004,4(8):592-603.
143. Fadeel, B.; Orrenius, S., Apoptosis:a basic biological phenomenon with wide-ranging implications in human disease. J. Intern. Med.2005,258(6):479-517.
144. Hoyer-Hansen, M.; Jaattela, M., Autophagy-An emerging target for cancer therapy. Autophagy 2008,4(5):574-580.
145. Gocheva, V.; Zeng, W.; Ke, D. X.; Klimstra, D.; Reinheckel, T.; Peters, C.; Hanahan, D.; Joyce, J. A., Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev.2006,20(5):543-556.
146. Fehrenbacher, N.; Jaattela, M., Lysosomes as targets for cancer therapy. Cancer Res. 2005,65(8):2993-2995.
147. Linder, S.; Shoshan, M. C., Lysosomes and endoplasmic reticulum:Targets for improved, selective anticancer therapy. Drug Resist. Updat.2005,8(4):199-204.
148. Roy, D.; Liston, D. R.; Idone, V. J.; Di, A.; Nelson, D. J.; Pujol, C.; Bliska, J. B.; Chakrabarti, S.; Andrews, N. W., A process for controlling intracellular bacterial infections induced by membrane injury. Science 2004,304(5676):1515-1518.
149. Kroemer, G.; Jaattela, M., Lysosomes and autophagy in cell death control. Nat. Rev. Cancer 2005,5(11):886-897.
150. Erdal, H.; Berndtsson, M.; Castro, J.; Brunk, U.; Shoshan, M. C.; Linder, S., Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. Proc. Natl. Acad. Sci. U. S. A.2005,102(1):192-197.
151. Groth-Pedersen, L.; Ostenfeld, M. S.; Hoyer-Hansen, M.; Nylandsted, J.; Jaattela, M., Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res.2007,67(5):2217-2225.
152. Parry, M. J.; Alakoskela, J. M. I.; Khandelia, H.; Kumar, S. A.; Jaattela, M.; Mahalka, A. K.; Kinnunen, P. K. J., High-affinity small molecule-phospholipid complex formation: Binding of siramesine to phosphatidic acid. J. Am. Chem. Soc.2008,130(39):12953-12960.
153. Ostenfeld, M. S.; Hoyer-Hansen, M; Bastholm, L.; Fehrenbacher, N.; Olsen, O. D.; Groth-Pedersen, L.; Puustinen, P.; Kirkegaard-Sorensen, T.; Nylandsted, J.; Farkas, T. Jaattela, M., Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy 2008,4(4):487-499.
154. Tao, Z. F.; Wang, L.; Stewart, K. D.; Chen, Z. H.; Gu, W.; Bui, M. H.; Merta, P.; Zhang, H. Y.; Kovar, P.; Johnson, E.; Park, C.; Judge, R.; Rosenberg, S.; Sowin, T.; Lin, N. H., Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. J. Med. Chem.2007,50(7):1514-1527.
155. Ingrassia, L.; Lefranc, F.; Kiss, R.; Mijatovic, T., Naphthalimides and Azonafides as Promising Anti-Cancer Agents. Curr. Med. Chem.2009,16(10):1192-1213.
156. Ratain, M. J.; Mick, R.; Berezin, F.; Janisch, L.; Schilsky, R. L.; Vogelzang, N. J.; Lane, L. B., Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res.1993, 53(10):2304-2308.
157. Brana, M. F.; Cacho, M.; Garcia, M. A.; de Pascual-Teresa, B.; Ramos, A.; Dominguez, M. T.; Pozuelo, J. M.; Abradelo, C.; Rey-Stolle, M. F.; Yuste, M.; Banez-Coronel, M.; Lacal, J. C, New analogues of amonafide and elinafide, containing aromatic heterocycles:Synthesis, antitumor activity, molecular modeling, and DNA binding properties. J. Med. Chem.2004, 47(6):1391-1399.
158. Antonini, I.; Santoni, G.; Lucciarini, R.; Amantini, C.; Sparapani, S.; Magnano, A., Synthesis and biological evaluation of new asymmetrical bisintercalators as potential antitumor drugs. J. Med. Chem.2006,49(24):7198-7207.
159. Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.; Ribaucour, F.; Simon, G.; Sauvage, S.; Gaussin, J. F.; Tuti, J.; El Yazidi, M.; Van Vynckt, F.; Mijatovic, T.; Lefranc, F.; Darro, F.; Kiss, R.,2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity. J. Med. Chem.2007, 50(17):4122-4134.
160. Tumiatti, V.; Milelli, A.; Minarini, A.; Rosini, M.; Bolognesi, M. L.; Micco, M.; Andrisano, V.; Bartolini, M.; Mancini, R; Recanatini, M.; Cavalli, A.; Melchiorre, C., Structure-Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone.4. Further Investigation on the Inner Spacer. J. Med. Chem.2008, 51(22):7308-7312.
161. Norton, J. T.; Witsch, M. A.; Luong, L.; Kawamura, A.; Ghosh, S.; Stack, M. S.; Sim, E.; Avram, M. J.; Appella, D. H.; Huang, S., Synthesis and anticancer activities of 6-amino amonafide derivatives. Anti-Cancer Drugs 2008,19(1):23-36.
162. Iranpoor, N.; Firouzabadi, H.; Aghapour, G.; Vaezzadeh, A. R., Triphenylphosphine /2,3-dichloro-5,6-dicyanobenzoquinone as a new, selective and neutral system for the facile conversion of alcohols, thiols and selenols to alkyl halides in the presence of halide ions. Tetrahedron 2002,58(43):8689-8693.
163. Xuhong, Q.; Zhenghua, Z.; Kongchang, C., A study on the Ullmann Condensation Reaction of 4-chloro-1,8-naphthalic anhydride with N, N-dimethylformamide. J. Prakt. Chem. /Chem-Ztg 1992,334(2):161-164.
164. Zhang, Z. C; Yang, Y. Y.; Zhang, D. N.; Wang, Y. Y.; Qian, X. H.; Liu, F. Y, Acenaphtho[1,2-b]pyrrole derivatives as new family of intercalators:Various DNA binding geometry and interesting antitumor capacity. Biorg. Med. Chem.2006,14(20):6962-6970.
165. Mizushima, T.; Natori, S.; Sekimizu, K., Relaxation of supercoiled DNA associated with induction of heat shock proteins in Escherichia coli. Mol. Gen. Genet.1993,238(1-2):1-5.
166. Wang, J. C, Cellular roles of DNA topoisomerases:A molecular perspective. Nat. Rev. Mol. CellBiol.2002,3(6):430-440.
167. Li, T. K.; Liu, L. F., Tumor cell death induced by topoisomerase-targeting drugs. Annu. Rev. Pharmacol. Toxicol.2001,41:53-77.
168. Larsen, A. K.; Eseargueil, A. E.; Skladanowski, A., Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol. Then 2003,99(2):167-181.
169. Tanabe, K.; Ikegami, Y; Ishida, R.; Andoh, T., Inhibition of Topoisomerase-II by antitumor agents bis(2,6-dioxopiperazine) derivatives. Cancer Res.1991,51(18):4903-4908.
170. Zdolsek, J. M.; Olsson, G. M.; Brunk, U. T., Photooxidative damage to lysosomes of cultured macrophages by acridine orange. Photochem. Photobiol.1990,51(1):67-76.
171. Yuan, X. M.; Li, W; Dalen, H.; Lotem, J.; Kama, R.; Sachs, L.; Brunk, U. T., Lysosomal destabilization in p53-induced apoptosis. Proc. Natl. Acad. Set U. S. A.2002,99(9): 6286-6291.
172. Green, D. R.; Reed, J. C., Mitochondria and apoptosis. Science 1998,281(5381): 1309-1312.
173. Garrido, C; Galluzzi, L.; Brunet, M.; Puig, P. E.; Didelot, C.; Kroemer, G., Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 2006,13(9):1423-1433.
174. Lim, M. L. R.; Chen, B. H.; Beart, P. M.; Nagley, P., Relative timing of redistribution of cytochrome c and Smac/DIABLO from mitochondria during apoptosis assessed by double immunocytochemistry on mammalian cells. Exp. Cell Res.2006,312(7):1174-1184.
175. Vermes, I.; Haanen, C; Steffensnakken, H.; Reutelingsperger, C., A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled Annexin V. J. Immunol. Methods 1995,184(1):39-51.
176. Riccardi, C.; Nicoletti, I., Analysis of apoptosis by propidium iodide staining and flow cytometry. Nature Protocols 2006,1:1458-1461.
177. Zhang, W. T.; Ruan, J. L.; Wu, P. F.; Jiang, F. C.; Zhang, L. N.; Fang, W.; Chen, X. L. Wang, Y.; Cao, B. S.; Chen, G. Y.; Zhu, Y. J.; Gu, J.; Chen, J. G, Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly (ADP-Ribose) Polymerase-1 Inhibitors. J. Med. Chem.2009,52(3):718-725.
178. Joo, S. S.; Yoo, Y. M., Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways:therapeutic implications for prostate cancer. J. Pineal Res.2009,47(1):8-14.
2. Thurston, D. E.;刘吉成译,Chemistry and Pharmacology of Anticancer Drugs (抗肿瘤药物的化学和药理学)北京：人民卫生出版社2008,9.
3.郭青龙,肿瘤药理学.北京：化学工业出版社2007,12.
4.胥彬,肿瘤药理学新论.北京：人民闻声出版社2004,5.
5. Hanahan, D.; Weinberg, R. A., The hallmarks of cancer. Cell 2000,100(1):57-70.
6. Ullrich, A., Tyrosine kinases as targets for cancer therapy. Clin. Cancer Res.2001,7(11): 3815s-3815s.
7. Levitzki, A.; Gazit, A., Tyrosine kinase inhibition:an approach to drug development. Science 1995,267(5205):1782-1788.
8. Baselga, J., Targeting tyrosine kinases in cancer:The second wave. Science 2006, 312(5777):1175-1178.
9. Cohen, P., Protein kinases--the major drug targets of the twenty-first century? Nat. Rev. Drug Discov.2002,1(4):309-315.
10. Schlessinger, J., Cell signaling by receptor tyrosine kinases. Cell 2000,103(2):211-225.
11. Noble, M. E. M.; Endicott, J. A.; Johnson, L. N., Protein kinase inhibitors:Insights into drug design from structure. Science 2004,303(5665):1800-1805.
12. Gschwind, A.; Fischer, O. M.; Ullrich, A., Timeline-The discovery of receptor tyrosine kinases:targets for cancer therapy. Nat. Rev. Cancer 2004,4(5):361-370.
13. Gschwind, A.; Fischer, O. M.; Ullrich, A., Receptor tyrosine kinases as targets for cancer therapy development. Insights into Receptor Function and New Drug Development Targets 2006:167-178.
14. Manetti, F.; Botta, M, Small-molecule inhibitors of fibroblast growth factor receptor (FGFR) tyrosine kinases (TK). Curr. Pharm. Des.2003,9(7):567-581.
15. Yarden, Y.; Sliwkowski, M. X., Untangling the ErbB signalling network. Nature Reviews Molecular Cell Biology 2001,2(2):127-137.
16. Antonello, A.; Tarozzi, A.; Morroni, F.; Cavalli, A.; Rosini, M.; Hrelia, P.; Bolognesi, M. L.; Melchiorre, C, Multitarget-directed drug design strategy:A novel molecule designed to block epidermal growth factor receptor (EGFR) and to exert proapoptotic effects. J Med Chem 2006,49(23):6642-6645.
17. Min, J. K.; Han, K. Y.; Kim, E. C.; Kim, Y. M.; Lee, S. W.; Kim, O. H.; Kim, K. W.; Gho, Y. S.; Kwon, Y. G., Capsaicin inhibits in vitro and in vivo angiogenesis. Cancer Res.2004, 64(2):644-651.
18. Kim, K. J.; Li, B.; Winer, J.; Armanini, M.; Gillett, N.; Phillips, H. S.; Ferrara, N., Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993,362(6423):841-844.
19. Mohammadi, M.; McMahon, G; Sun, L.; Tang, C.; Hirth, P.; Yeh, B. K.; Hubbard, S. R.; Schlessinger, J., Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 1997,276(5314):955-960.
20. Knights, V.; Cook, S. J., De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol. Then 2010,125(1):105-117.
21. Thompson, A. M; Connolly, C. J. C; Hamby, J. M.; Boushelle, S.; Hartl, B. G; Amar, A. M.; Kraker, A. J.; Driscoll, D. L.; Steinkampf, R. W.; Patmore, S. J.; Vincent, P. W.; Roberts, B. J.; Elliott, W. L.; Klohs, W.; Leopold, W. R.; Showalter, H. D. H.; Denny, W. A., 3-(3,5-dimethoxyphenyl)-1,6-naphthyridine-2,7-diamines and related 2-urea derivatives are potent and selective inhibitors of the FGF receptor-1 tyrosine kinase. J. Med. Chem.2000, 43(22):4200-4211.
22. Lokker, N. A.; Sullivan, C. M.; Hollenbach, S. J.; Israel, M. A.; Giese, N. A., Platelet-derived growth factor (PDGF) autocrine signaling regulates survival and mitogenic pathways in glioblastoma cells:Evidence that the novel PDGF-C and PDGF-D ligands may play a role in the development of brain tumors. Cancer Res.2002,62(13):3729-3735.
23. Levin, M.; D'Souza, N.; Castaner, J., Iressa (TM). Oncolytic, EGF receptor tyrosine kinase inhibitor. Drugs of the Future 2002,27(4):339-345.
24. Konecny, G. E.; Venkatesan, N.; Yang, G.; Dering, J.; Ginther, C.; Finn, R.; Rahmeh, M.; Fejzo, M. S.; Toft, D.; Jiang, S. W.; Slamon, D. J.; Podratz, K. C, Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells. Br. J. Cancer 2008, 98(6):1076-1084.
25. Erlichman, C; Hidalgo, M.; Boni, J. P.; Martins, P.; Quinn, S. E.; Zacharchuk, C.; Amorusi, P.; Adjei, A. A.; Rowinsky, E. K., Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J. Clin. Oncol.2006,24(15):2252-2260.
26. Rabindran, S. K.; Discafani, C. M.; Rosfjord, E. C.; Baxter, M.; Floyd, M. B.; Golas, J.; Hallett, W. A.; Johnson, B. D.; Nilakantan, R.; Overbeek, E.; Reich, M. F.; Shen, R.; Shi, X. Q.; Tsou, H. R.; Wang, Y. F.; Wissner, A., Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res.2004,64(11):3958-3965.
27. Golas, J. M.; Arndt, K.; Etienne, C; Lucas, J.; Nardin, D.; Gibbons, J.; Frost, P.; Ye, F.; Boschelli, D. H.; Boschelli, F., SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res.2003, 63(2):375-381.
28. Laird, A. D.; Vajkoczy, P.; Shawver, L. K.; Thurnher, A.; Liang, C.; Mohammadi, M.; Schlessinger, J.; Ullrich, A.; Hubbard, S. R.; Blake, R. A.; Fong, T. A. T.; Strawn, L. M.; Sun, L.; Tang, C.; Hawtin, R.; Tang, F.; Shenoy, N.; Hirth, K. P.; McMahon, G.; Cherrington, J. M., SU6668 is a potent antiangiogenic and antitumor agent that induces regression of established tumors. Cancer Res.2000,60(15):4152-4160.
29. Motzer, R. J.; Rini, B. I.; Bukowski, R. M.; Curti, B. D.; George, D. J.; Hudes, G R.; Redman, B. G.; Margolin, K. A.; Merchan, J. R.; Wilding, G.; Ginsberg, M. S.; Bacik, J.; Kim, S. T.; Baum, C. M.; Michaelson, M. D., Sunitinib in patients with metastatic renal cell carcinoma. Jama-Journal of the American Medical Association 2006,295(21):2516-2524.
30. Weisberg, E.; Manley, P. W.; Cowan-Jacob, S. W.; Hochhaus, A.; Griffin, J. D., Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat. Rev. Cancer 2007,7(5):345-356.
31. Hochhaus, A.; Kantarjian, H. M.; Baccarani, M.; Lipton, J. H.; Apperley, J. F.; Druker, B. J.; Facon, T.; Goldberg, S. L.; Cervantes, F.; Niederwieser, D.; Silver, R. T.; Stone, R. M.; Hughes, T. P.; Muller, M. C.; Ezzeddine, R.; Countouriotis, A. M.; Shah, N. P., Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007,109(6):2303-2309.
32. Yokoi, K.; Thaker, P. H.; Yazici, S.; Rebhun, R. R.; Nam, D. H.; He, J. Q.; Kim, S. J.; Abbruzzese, J. L.; Hamilton, S. R.; Fidler, I. J., Dual inhibition of epidermal growth factor receptor and vascular endothelial growth factor receptor phosphorylation by AEE788 reduces growth and metastasis of human colon carcinoma in an orthotopic nude mouse model. Cancer Res.2005,65(9):3716-3725.
33. Traxler, P.; Allegrini, P. R.; Brandt, R.; Brueggen, J.; Cozens, R.; Fabbro, D.; Grosios, K.; Lane, H. A.; McSheehy, P.; Mestan, J.; Meyer, T.; Tang, C.; Wartmann, M.; Wood, J.; Caravatti, G., AEE788:A dual family epidermal growth factor receptor/ErbB2 and vascular endothelial growth factor receptor tyrosine kinase inhibitor with antitumor and antiangiogenic activity. Cancer Res.2004,64(14):4931-4941.
34. Rixe, O.; Bukowski, R. M.; Michaelson, M. D.; Wilding, G.; Hudes, G R.; Bolte, O.; Motzer, R. J.; Bycott, P.; Liou, K. F.; Freddo, J.; Trask, P. C.; Kim, S.; Rini, B. I., Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer:a phase Ⅱ study. Lancet Oncology 2007,8(11):975-984.
35. Sonpavde, G; Hutson, T. E., Pazopanib:a novel multitargeted tyrosine kinase inhibitor. Curr Oncol Rep 2007,9(2):115-119.
36. Wilhelm, S.; Carter, C.; Lynch, M.; Lowinger, T.; Dumas, J.; Smith, R. A.; Schwartz, B.; Simantov, R.; Kelley, S., Discovery and development of sorafenib:a multikinase inhibitor for treating cancer. Nature Reviews Drug Discovery 2006,5(10):835-844.
37. Beebe, J. S.; Jani, J. P.; Knauth, E.; Goodwin, P.; Higdon, C.; Rossi, A. M.; Emerson, E.; Finkelstein, M.; Floyd, E.; Harriman, S.; Atherton, J.; Hillerman, S.; Soderstrom, C.; Kou, K.; Gant, T.; Noe, M. C.; Foster, B.; Rastinejad, F.; Marx, M. A.; Schaeffer, T.; Whalen, P. M.; Roberts, W. G., Pharmacological characterization of CP-547,632, a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for cancer therapy. Cancer Res.2003, 63(21):7301-7309.
38. Hurley, L. H., DNA and its associated processes as targets for cancer therapy. Nat. Rev. Cancer 2002,2(3):188-200.
39. Brana, M. F.; Cacho, M.; Gradillas, A.; de Pascual-Teresa, B.; Ramos, A., Intercalators as anticancer drugs. Curr. Pharm. Des.2001,7(17):1745-1780.
40.吴爱斌,新颖萘酰亚胺类抗肿瘤剂的设计合成与生物性能：(博士学位论文).上海：华东理工大学2009.
41.殷红,新型萘酰亚胺类抗肿瘤药物先导的设计、合成及构效关系研究：(博士学位论文).上海：华东理工大学2006.
42. Krapcho, A. P.; Getahun, Z.; Avery, K. L.; Vargas, K. J.; Hacker, M. P.; Spinelli, S.; Pezzoni, G.; Manzotti, C, Synthesis and antitumor evaluations of symmetrically and unsymmetrically substituted 1,4-bis[(aminoalkyl)amino]anthracene-9,10-diones and 1,4-bis[(aminoalkyl)amino]-5,8-dihydroxyanthracene-9,10-diones. J. Med. Chem.1991,34(8): 2373-2380.
43. Xiao, Y.; Liu, F.; Qian, X.; Cui, J., A new class of long-wavelength fluorophores:strong red fluorescence, convenient synthesis and easy derivation. Chem. Commun.2005, (2): 239-241.
44. Zhang, Z.; Yang, Y.; Zhang, D.; Wang, Y.; Qian, X.; Liu, F., Acenaphtho[1,2-b]pyrrole derivatives as new family of intercalators:Various DNA binding geometry and interesting antitumor capacity. Bioorg. Med. Chem.2006,14(20):6962-6970.
45. Brana, M. F.; Ramos, A., Naphthalimides as anti-cancer agents:Synthesis and biological activity. Curr. Med. Chem.:Anti-Cancer Agents 2001,1(3):237-255.
46. Sami, S. M.; Dorr, R. T.; Solyom, A. M.; Alberts, D. S.; Remers, W. A., Amino-Substituted 2-[2-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. Synthesis, Antitumor Activity, and Quantitative Structure-Activity Relationship. J. Med. Chem.1995,38(6):983-993.
47. Sami, S. M.; Dorr, R. T.; Alberts, D. S.; Remers, W. A.,2-Substituted 1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones. A new class of antitumor agent. J. Med. Chem.1993,36(6):765-770.
48. Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.; Ribaucour, F.; Simon, G.; Sauvage, S.; Gaussin, J. F.; Tuti, J.; El Yazidi, M.; Van Vynckt, F.; Mijatovic, T.; Lefranc, R; Darro, F.; Kiss, R.,2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin5-yl} carbamoyl) acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity. J. Med. Chem.2007,50(17): 4122-4134.
49. Bousquet, P. F.; Brana, M. F.; Conlon, D.; Fitzgerald, K. M.; Perron, D.; Cocchiaro, C.; Miller, R.; Moran, M.; George, J.; Qian, X. D., Preclinical evaluation of LU 79553:a novel bis-naphthalimide with potent antitumor activity. Cancer Res.1995,55(5):1176-1180.
50. McRipley, R. J.; Burns-Horwitz, P. E.; Czerniak, P. M.; Diamond, R. J.; Diamond, M. A.; Miller, J. L.; Page, R. J.; Dexter, D. L.; Chen, S. F.; Sun, J. H., Efficacy of DMP 840:a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity. Cancer Res. 1994,54(1):159-164.
51. Qian, X. H.; Li, Z. G.; Yang, Q., Highly efficient antitumor agents of heterocycles containing sulfur atom:Linear and angular thiazonaphthalimides against human lung cancer cell in vitro. Biorg. Med. Chem.2007,15(21):6846-6851.
52. Li, F.; Cui, J. N.; Guo, L. Y.; Qian, X. H.; Ren, W. M.; Wang, K. W.; Liu, F.Y, Molecular design, chemical synthesis, and biological evaluation of'4-1'pentacyclic aryl/heteroaryl-imidazonaphthalimides. Biorg. Med. Chem.2007,15(15):5114-5121.
53. Li, Y. G.; Xu, Y. F.; Qian, X. H.; Qu, B., Naphthalimide-thiazoles as novel photonucleases: molecular design, synthesis, and evaluation. Tetrahedron Lett.2004,45(6):1247-1251.
54. Li, Z. G.; Yang, Q.; Qian, X. H., Synthesis, antitumor and DNA photocleaving activities of novel naphthalene carboxamides:effects of different thio-heterocyclic rings and aminoalkyl side chains. Tetrahedron 2005,61(36):8711-8717.
55. Li, Z. G.; Yang, Q.; Qian, X. H., Novel thiazonaphthalimides as efficient antitumor and DNA photocleaving agents:Effects of intercalation, side chains, and substituent groups. Biorg. Med. Chem.2005,13(16):4864-4870.
56. Ott, I.; Xu, Y. F.; Liu, J. W.; Kokoschka, M.; Harlos, M.; Sheldrick, W. S.; Qian, X. H., Sulfur-substituted naphthalimides as photoactivatable anticancer agents:DNA interaction, fluorescence imaging, and phototoxic effects in cultured tumor cells. Biorg. Med. Chem.2008, 16(15):7107-7116.
57. Wu, A. B.; Xu, Y. F.; Qian, X. H., Novel naphthalimide-amino acid conjugates with flexible leucine moiety as side chain:Design, synthesis and potential antitumor activity. Biorg. Med. Chem.2009,17(2):592-599.
58. Wu, A. B.; Xu, Y. F.; Qian, X. H.; Wang, J.; Liu, J. W., Novel naphthalimide derivatives as potential apoptosis-inducing agents:Design, synthesis and biological evaluation. Eur. J. Med. Chem.2009,44(11):4674-4680.
59. Yang, Q.; Yang, P.; Qian, X. H.; Tong, L. P., Naphthalimide intercalators with chiral amino side chains:Effects of chirality on DNA binding, photodamage and antitumor cytotoxicity. Bioorg. Med. Chem. Lett.2008,18(23):6210-6213.
60. Zhang, W.; Qian, X. H.; Wu, Y. L.; Ohrui, H., A new class of DNA intercalator and photocleaver:Bis-naphthailimides with bromo and nitro substituents. Heterocycl. Commun. 2003,9(3):229-234.
61. Zhu, H.; Huang, M; Yang, F.; Chen, Y; Miao, Z. H.; Qian, X. H.; Xu, Y. F.; Qin, Y. X.; Luo, H. B.; Shen, X.; Geng, M. Y; Cai, Y J.; Ding, J., R16, a novel amonafide analogue, induces apoptosis and G(2)-M arrest via poisoning topoisomerase Ⅱ. Mol. Cancer Then 2007, 6(2):484-495.
62. Hurley, L. H., DNA and its associated processes as targets for cancer therapy. Nature Reviews Cancer 2002,2(3):188-200.
63. Moore, M. J. B.; Schultes, C. M.; Cuesta, J.; Cuenca, F.; Gunaratnam, M.; Tanious, F.A.; Wilson, W. D.; Neidle, S., Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3,6-and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation. J. Med. Chem.2006,49(2):582-599.
64. Leonetti, C.; Scarsella, M.; Riggio, G.; Rizzo, A.; Salvati, E.; D'Incalci, M.; Staszewsky, L.; Frapolli, R.; Stevens, M. F.; Stoppacciaro, A.; Mottolese, M.; Antoniani, B.; Gilson, E.; Zupi, G.; Biroccio, A., G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors. Clin. Cancer Res.2008,14(22): 7284-7291.
65. Zhou, J. L.; Lu, Y. J.; Ou, T. M.; Zhou, J. M.; Huang, Z. S.; Zhu, X. R.; Du, C. J.; Bu, X. Z.; Ma, L.; Gu, L. Q.; Li, Y M.; Chan, A. S. C, Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase. J. Med. Chem.2005,48(23):7315-7321.
66. Huang, J.; Li, G. R.; Wu, Z. G.; Song, Z. B.; Zhou, Y.Y.; Shuai, L.; Weng, X. C; Zhou, X.; Yang, G. F., Bisbenzimidazole to benzobisimidazole:from binding B-form duplex DNA to recognizing different modes of telomere G-quadruplex. Chem. Commun.2009, (8):902-904.
67. Seenisamy, J.; Bashyam, S.; Gokhale, V.; Vankayalapati, H.; Sun, D.; Siddiqui-Jain, A.; Streiner, N.; Shin-ya, K.; White, E.; Wilson, W. D.; Hurley, L. H., Design and synthesis of an expanded porphyrin that has selectivity for the c-MYC G-quadruplex structure. J. Am. Chem. Soc.2005,127(9):2944-2959.
68. De Cian, A.; DeLemos, E.; Mergny, J. L.; Teulade-Fichou, M. P.; Monchaud, D., Highly efficient G-quadruplex recognition by bisquinolinium compounds. J. Am. Chem. Soc.2007, 129(7):1856-1857.
69. Sun, D.; Thompson, B.; Cathers, B. E.; Salazar, M.; Kerwin, S. M.; Trent, J. O.; Jenkins, T. C.; Neidle, S.; Hurley, L. H., Inhibition of human telomerase by a G-quadruplex-interactive compound. J. Med. Chem.1997,40(14):2113-2116.
70. Anantha, N. V.; Azam, M.; Sheardy, R. D., Porphyrin Binding to Quadruplexed T4G4. Biochemistry (Mosc).1998,37(9):2709-2714.
71. Wheelhouse, R. T.; Sun, D.; Han, H.; Han, F. X.; Hurley, L. H., Cationic Porphyrins as Telomerase Inhibitors:the Interaction of Tetra-(N-methyl-4-pyridyl)porphine with Quadruplex DNA. J. Am. Chem. Soc.1998,120(13):3261-3262.
72. Kim, M. Y.; Gleason-Guzman, M.; Izbicka, E.; Nishioka, D.; Hurley, L. H., The different biological effects of telomestatin and TMPyP4 can be attributed to their selectivity for interaction with intramolecular or intermolecular G-quadruplex structures. Cancer Res.2003, 63(12):3247-3256.
73. Fedoroff, O. Y.; Salazar, M.; Han, H.; Chemeris, V. V.; Kerwin, S. M.; Hurley, L. H., NMR-Based Model of a Telomerase-Inhibiting Compound Bound to G-Quadruplex DNAf. Biochemistry (Mosc).1998,37(36):12367-12374.
74. Han, H.; Cliff, C. L.; Hurley, L. H., Accelerated Assembly of G-Quadruplex Structures by a Small Moleculet. Biochemistry (Mosc).1999,38(22):6981-6986.
75. Kern, J. T.; Thomas, P. W.; Kerwin, S. M., The relationship between ligand aggregation and G-quadruplex DNA selectivity in a series of 3,4,9,10-perylenetetracarboxylic acid diimides. Biochemistry (Mosc).2002,41(38):11379-11389.
76. Guo, Q.; Lu, M.; Marky, L. A.; Kallenbach, N. R., Interaction of the dye ethidium bromide with DNA containing guanine repeats. Biochemistry (Mosc).1992,31(9): 2451-2455.
77. Teulade-Fichou, M. P.; Carrasco, C; Guittat, L.; Bailly, C; Alberti, P.; Mergny, J. L.; David, A.; Lehn, J. M.; Wilson, W. D., Selective recognition of G-quadruplex telomeric DNA by a bis(quinacridine) macrocycle. .. Am. Chem. Soc.2003,125(16):4732-4740.
78. Liu, W.; Bulgaru, A.; Haigentz, M.; Stein, C. A.; Perez-Soler, R.; Mani, S., The BCL2-family of protein ligands as cancer drugs:the next generation of therapeutics. Curr Med Chem Anticancer Agents 2003,3(3):217-223.
79. Manion, M. K.; Fry, J.; Schwartz, P. S.; Hockenbery, D. M, Small-molecule inhibitors of Bcl-2. Current opinion in investigational drugs (London, England:2000) 2006,7(12): 1077-1084.
80. Doshi, J. M; Tian, D. F.; Xing, C. G, Structure-activity relationship studies of ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA 14-1), an antagonist for antiapoptotic Bcl-2 proteins to overcome drug resistance in cancer. J. Med. Chem.2006,49(26):7731-7739.
81. Chan, S. L.; Lee, M. C; Tan, K. O.; Yang, L. K.; Lee, A. S. Y.; Flotow, H.; Fu, N. Y; Butler, M. S.; Soejarto, D. D.; Buss, A. D.; Yu, V. C., Identification of chelerythrine as an inhibitor of BclXL function. J. Biol. Chem.2003,278(23):20453-20456.
82. Degterev, A.; Lugovskoy, A.; Cardone, M; Mulley, B.; Wagner, G.; Mitchison, T.; Yuan, J. Y, Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-x(L). Nat. Cell Biol.2001,3(2):173-182.
83. Oltersdorf, T.; Elmore, S. W.; Shoemaker, A. R.; Armstrong, R. C.; Augeri, D. J.; Belli, B. A.; Bruncko, M.; Deckwerth, T. L.; Dinges, J.; Hajduk, P. J.; Joseph, M. K.; Kitada, S.; Korsmeyer, S. J.; Kunzer, A. R.; Letai, A.; Li, C; Mitten, M. J.; Nettesheim, D. G.; Ng, S.; Nimmer, P. M.; O'Connor, J. M.; Oleksijew, A.; Petros, A. M.; Reed, J. C.; Shen, W.; Tahir, S. K.; Thompson, C. B.; Tomaselli, K. J.; Wang, B. L.; Wendt, M. D.; Zhang, H. C; Fesik, S. W.; Rosenberg, S. H., An inhibitor of Bel-2 family proteins induces regression of solid tumours. Nature 2005,435(7042):677-681.
84. van Delft, M. R.; Wei, A. H.; Mason, K. D.; Vandenberg, C. J.; Chen, L.; Czabotar, P. E.; Willis, S. N.; Scott, C. L.; Day, C. L.; Cory, S.; Adams, J. M.; Roberts, A. W.; Huang, D. C. S., The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006,10(5):389-399.
85. Wang, Y.; Serradell, N.; Bolos, J.; Rosa, E., Obatoclax mesilate-Bcl-2 inhibitor, apoptosis inducer, oncolytic. Drugs of the Future 2007,32(3):228-233.
86. Tang, G. Z.; Nikolovska-Coleska, Z.; Qiu, S.; Yang, C. Y.; Guo, J.; Wang, S. M., Acylpyrogallols as inhibitors of antiapoptotic Bcl-2 proteins. J. Med. Chem.2008,51(4): 717-720.
87. Zhang, Z.; Jin, L.; Qian, X.; Wei, M.; Wang, Y.; Wang, J.; Yang, Y.; Xu, Q.; Xu, Y; Liu, F., Novel Bcl-2 inhibitors:discovery and mechanism study of small organic apoptosis-inducing agents. ChemBioChem 2007,8(1):113-121.
88. Boya, P.; Andreau, K.; Poncet, D.; Zamzami, N.; Perfettini, J. L.; Metivier, D.; Ojcius, D. M.; Jaattela, M.; Kroemer, G, Lysosomal membrane permeabilization induces cell death in a mitochondrion-dependent fashion. J. Exp. Med.2003,197(10):1323-1334.
89. Boya, P.; Kroemer, G, Lysosomal membrane permeabilization in cell death. Oncogene 2008,27(50):6434-6451.
90. Kagedal, K.; Zhao, M.; Svensson, I.; Brunk, U. T., Sphingosine-induced apoptosis is dependent on lysosomal proteases. Biochem. J2001,359:335-343.
91. Ostenfeld, M. S.; Fehrenbacher, N.; Hoyer-Hansen, M.; Thomsen, C.; Farkas, T.; Jaattela, M., Effective tumor cell death by sigma-2 receptor ligand siramesine involves lysosomal leakage and oxidative stress. Cancer Res.2005,65(19):8975-8983.
92. Boya, P.; Gonzalez-Polo, R. A.; Poncet, D.; Andreau, K.; Vieira, H. L. A.; Roumier, T.; Perfettini, J. L.; Kroemer, G, Mitochondrial membrane permeabilization is a critical step of lysosome-initiated apoptosis induced by hydroxychloroquine. Oncogene 2003,22(25): 3927-3936.
93. Uchimoto, T.; Nohara, H.; Kamehara, R.; Iwamura, M.; Watanabe, N.; Kobayashi, Y., Mechanism of apoptosis induced by a lysosomotropic agent, L-Leucyl-L-leucine methyl ester. Apoptosis 1999,4(5):357-362.
94. Li, W.; Yuan, X. M.; Nordgren, G; Dalen, H.; Dubowchik, G. M; Firestone, R. A.; Brunk, U. T., Induction of cell death by the lysosomotropic detergent MSDH. FEBS Lett.2000, 470(1):35-39.
95. Yu, Z. Q.; Wei, L.; Brunk, U. T.,3-aminopropanal is a lysosomotropic aldehyde that causes oxidative stress and apoptosis by rupturing lysosomes. APMIS 2003,111(6):643-652.
96. Sawyers, C., Targeted cancer therapy. Nature 2004,432(7015):294-297.
97. Arora, A.; Scholar, E. M., Role of tyrosine kinase inhibitors in cancer therapy. J. Pharmacol. Exp. Ther.2005,315(3):971-979.
98. Zwick, E.; Bange, J.; Ullrich, A., Receptor tyrosine kinases as targets for anticancer drugs. Trends Mol. Med.2002,8(1):17-23.
99. Traxler, P.; Bold, G.; Buchdunger, E.; Caravatti, G.; Furet, P.; Manley, P.; O'Reilly, T. Wood, J.; Zimmermann, J., Tyrosine kinase inhibitors:From rational design to clinical trials. Med. Res. Rev.2001,21(6):499-512.
100. Zhang, J. M.; Yang, P. L.; Gray, N. S., Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer 2009,9(1):28-39.
101. Borzilleri, R. M.; Zheng, X. P.; Qian, L. G.; Ellis, C.; Cai, Z. W.; Wautlet, B. S.; Mortillo, S.; Jeyaseelan, R.; Kukral, D. W.; Fura, A.; Kamath, A.; Vyas, V.; Tokarski, J. S.; Barrish, J. C.; Hunt, J. T.; Lombardo, L. J.; Fargnoli, J.; Bhide, R. S., Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f] [1,2,4] triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. J. Med. Chem.2005,48(12):3991-4008.
102. Gu, X.; Wang, Y.; Kumar, A.; Ye, G.; Parang, K.; Sun, G, Design and evaluation of hydroxamate derivatives as metal-mediated inhibitors of a protein tyrosine kinase. J. Med. Chem.2006,49(25):7532-7539.
103. Tao, Z. F.; Hasvold, L. A.; Leverson, J. D.; Han, E. K.; Guan, R.; Johnson, E. F.; Stoll, V. S.; Stewart, K. D.; Stamper, G.; Soni, N.; Bouska, J. J.; Luo, Y.; Sowin, T. J.; Lin, N. H.; Giranda, V. S.; Rosenberg, S. H.; Penning, T. D., Discovery of 3H-benzo[4,5]thieno[3,2-d] pyrimidin-4-ones as potent, highly selective, and orally bioavailable inhibitors of the human protooncogene proviral insertion site in moloney murine leukemia virus (PIM) kinases. J. Med. Chem.2009,52(21):6621-6636.
104. Frey, R. R.; Curtin, M. L.; Albert, D. H.; Glaser, K. B.; Pease, L. J.; Soni, N. B.; Bouska, J. J.; Reuter, D.; Stewart, K. D.; Marcotte, P.; Bukofzer, G.; Li, J.; Davidsen, S. K.; Michaelides, M. R.,7-Aminopyrazolo[1,5-a]pyrimidines as potent multitargeted receptor tyrosine kinase inhibitors. J. Med. Chem.2008,51(13):3777-3787.
105. Fabbro, D.; Manley, P. W., Su-6668. SUGEN. Curr. Opin. Investig. Drugs 2001,2(8): 1142-1148.
106. Marek, L.; Ware, K. E.; Fritzsche, A.; Hercule, P.; Helton, W. R.; Smith, J. E.; McDermott, L. A.; Coldren, C. D.; Nemenoff, R. A.; Merrick, D. T.; Helfrich, B. A.; Bunn, P. A.; Heasley, L. E., Fibroblast Growth Factor (FGF) and FGF Receptor-Mediated Autocrine Signaling in Non-Small-Cell Lung Cancer Cells. Mol. Pharmacol.2009,75(1):196-207.
107. Coskun, A.; Deniz Yilmaz, M.; Akkaya, E. U., An acenaphthopyrrolone-dipicolylamine derivative as a selective and sensitive chemosensor for group IIB cations. Tetrahedron Lett. 2006,47(22):3689-3691.
108. Zhang, M.; Yu, M.; Li, F.; Zhu, M.; Li, M.; Gao, Y.; Li, L.; Liu, Z.; Zhang, J.; Zhang, D.; Yi, T.; Huang, C, A Highly Selective Fluorescence Turn-on Sensor for Cysteine/Homocysteine and Its Application in Bioimaging. J. Am. Chem. Soc.2007,129(34): 10322-10323.
109. Liu, Y.; Xu, Y.; Qian, X.; Xiao, Y.; Liu, J.; Shen, L.; Li, J.; Zhang, Y, Synthesis and evaluation of novel 8-oxo-8H-cyclopenta[a]acenaphthylene-7-carbonitriles as long-wavelength fluorescent markers for hypoxic cells in solid tumor. Bioorg. Med. Chem. Lett.2006,16(6):1562-1566.
110. Xiong, L.; Yu, M.; Cheng, M.; Zhang, M.; Zhang, X.; Xu, C.; Li, F., A photostable fluorescent probe for targeted imaging of tumor cells possessing integrin alpha vbeta 3**. Mol. BioSyst.2009,5(3):241-243.
111. Liu, F.; Xiao, Y.; Qian, X.; Zhang, Z.; Cui, J.; Cui, D.; Zhang, R., Versatile acenaphtho[1,2-b]pyrrole-carbonitriles as a new family of heterocycles:diverse SNArH reactions, cytotoxicity and spectral behavior. Tetrahedron 2005,61(47):11264-11269.
112. Liu, F.; Qian, X.; Cui, J.; Xiao, Y.; Zhang, R.; Li, G, Design, synthesis, and antitumor evaluation of novel acenaphtho[1,2-b]pyrrole-carboxylic acid esters with amino chain substitution. Bioorg. Med. Chem.2006,14(13):4639-4644.
113. Wu, X. J.; Kassie, F.; Mersch-Sundermann, V., Induction of apoptosis in tumor cells by naturally occurring sulfur-containing compounds. Mutat. Res.-Rev. Mut. Res.2005,589(2): 81-102.
114. Aggarwal, B. B.; Shishodia, S., Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol.2006,71(10):1397-1421.
115. Isanbor, C.; O'Hagan, D., Fluorine in medicinal chemistry:A review of anti-cancer agents. J. Fluorine Chem.2006,127(3):303-319.
116. Hagmann, W. K., The many roles for fluorine in medicinal chemistry. J. Med. Chem. 2008,51(15):4359-4369.
117. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V., Fluorine in medicinal chemistry. Chem. Soc. Rev.2008,37(2):320-330.
118. Bohm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-Sander, U.; Stahl, M., Fluorine in medicinal chemistry. ChemBioChem 2004,5(5):637-643.
119.刘凤玉,新苊并杂环发色团及其衍生物的合成、光谱及其作为DNA靶向分子的研究：(博士学位论文).大连：大连理工大学2006.
120. Petrelli, A.; Giordano, S., From single-to multi-target drugs in cancer therapy:When aspecificity becomes an advantage. Curr. Med. Chem.2008,15(5):422-432.
121. Fu, Z.; Malureanu, L.; Huang, J.; Wang, W.; Li, H.; Van Deursen, J. M.; Tindall, D. J.; Chen, J., Plkl-dependent phosphorylation of FoxMl regulates a transcriptional programme required for mitotic progression. Nat. Cell Biol 2008,10(9):1076-1082.
122. Overington, J. P.; Al-Lazikani, B.; Hopkins, A. L., Opinion-How many drug targets are there? Nat. Rev. Drug Discov.2006,5(12):993-996.
123. Szuromi, P.; Vinson, V.; Marshall, E., Rethinking drug discovery-Introduction. Science 2004,303(5665):1795-1795.
124. Osterborg, A.; Mellstedt, H.; Keating, M., Clinical effects of alemtuzumab (Campath-1H) in B-cell chronic lymphocytic leukemia. Med. Oncol.2002,19:S21-S26.
125. Bode, A. M.; Dong, Z. G, Cancer prevention research-then and now. Nat. Rev. Cancer 2009,9(7):508-516.
126. Zhan, P.; Liu, X. Y., Designed multiple ligands:an emerging anti-HIV drug discovery paradigm. Curr. Pharm. Des.2009,15(16):1893-1917.
127. Van der Schyf, C. J.; Geldenhuys, W. J., Polycyclic compounds:ideal drug scaffolds for the design of multiple mechanism drugs? Neurotherapeutics 2009,6(1):175-186.
128. Futerman, A. H.; Sussman, J. L.; Horowitz, M.; Silman, I.; Zimran, A., New directions in the treatment of Gaucher disease. Trends Pharmacol. Sci.2004,25(3):147-151.
129. Schrattenholz, A.; Soskic, V, What does systems biology mean for drug development? Curr. Med. Chem.2008,15(15):1520-1528.
130. Borisy, A. A.; Elliott, P. J.; Hurst, N. W.; Lee, M. S.; Lehar, J.; Price, E. R.; Serbedzija, G; Zimmermann, G. R.; Foley, M. A.; Stockwell, B. R.; Keith, C. T., Systematic discovery of multicomponent therapeutics. Proc. Natl. Acad. Sci. U. S. A.2003,100(13):7977-7982.
131. Zimmermann, G. R.; Lehar, J.; Keith, C. T., Multi-target therapeutics:when the whole is greater than the sum of the parts. Drug Discov. Today 2007,12(1-2):34-42.
132. Van der Greef, J.; McBurney, R. N., Innovation-Rescuing drug discovery:in vivo systems pathology and systems pharmacology. Nat. Rev. Drug Discov.2005,4(12):961-967.
133. Morphy, R.; Rankovic, Z., Designed multiple ligands. An emerging drug discovery paradigm. J. Med. Chem.2005,48(21):6523-6543.
134. Wei, D. G.; Jiang, X. L.; Zhou, L.; Chen, J.; Chen, Z.; He, C.; Yang, K.; Liu, Y.; Pei, J. R.; Lai, L. H., Discovery of Multitarget Inhibitors by Combining Molecular Docking with Common Pharmacophore Matching. J. Med. Chem.2008,51(24):7882-7888.
135. Hopkins, A. L., Network pharmacology:the next paradigm in drug discovery. Nat. Chem. Biol.2008,4(11):682-690.
136. Kerr, J. F. R.; Wyllie, A. H.; Currie, A. R., Apoptosis:a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972,26(4):239-257.
137. Fischer, U.; Janssen, K.; Schulze-Osthoff, K., Cutting-edge apoptosis-based therapeutics-A panacea for cancer? Biodrugs 2007,21(5):273-297.
138. Thompson, C. B., Apoptosis in the pathogenesis and treatment of disease. Science 1995, 267(5203):1456-1462.
139. Reed, J. C., Apoptosis-based therapies. Nat. Rev. Drug Discoo.2002,1(2):111-121.
140. Kroemer, G.; Galluzzi, L.; Brenner, C., Mitochondrial membrane permeabilization in cell death. Physiol. Rev.2007,87(1):99-163.
141. Tian, Z. Y.; Xie, S. Q.; Du, Y. W.; Ma, Y F.; Zhao, J.; Gao, W. Y.; Wang, C. J., Synthesis, cytotoxicity and apoptosis of naphthalimide polyamine conjugates as antitumor agents. Eur. J. Med. Chem.2009,44(1):393-399.
142. Okada, H.; Mak, T. W., Pathways of apoptotic and non-apoptotic death in tumour cells. Nat. Rev. Cancer 2004,4(8):592-603.
143. Fadeel, B.; Orrenius, S., Apoptosis:a basic biological phenomenon with wide-ranging implications in human disease. J. Intern. Med.2005,258(6):479-517.
144. Hoyer-Hansen, M.; Jaattela, M., Autophagy-An emerging target for cancer therapy. Autophagy 2008,4(5):574-580.
145. Gocheva, V.; Zeng, W.; Ke, D. X.; Klimstra, D.; Reinheckel, T.; Peters, C.; Hanahan, D.; Joyce, J. A., Distinct roles for cysteine cathepsin genes in multistage tumorigenesis. Genes Dev.2006,20(5):543-556.
146. Fehrenbacher, N.; Jaattela, M., Lysosomes as targets for cancer therapy. Cancer Res. 2005,65(8):2993-2995.
147. Linder, S.; Shoshan, M. C., Lysosomes and endoplasmic reticulum:Targets for improved, selective anticancer therapy. Drug Resist. Updat.2005,8(4):199-204.
148. Roy, D.; Liston, D. R.; Idone, V. J.; Di, A.; Nelson, D. J.; Pujol, C.; Bliska, J. B.; Chakrabarti, S.; Andrews, N. W., A process for controlling intracellular bacterial infections induced by membrane injury. Science 2004,304(5676):1515-1518.
149. Kroemer, G.; Jaattela, M., Lysosomes and autophagy in cell death control. Nat. Rev. Cancer 2005,5(11):886-897.
150. Erdal, H.; Berndtsson, M.; Castro, J.; Brunk, U.; Shoshan, M. C.; Linder, S., Induction of lysosomal membrane permeabilization by compounds that activate p53-independent apoptosis. Proc. Natl. Acad. Sci. U. S. A.2005,102(1):192-197.
151. Groth-Pedersen, L.; Ostenfeld, M. S.; Hoyer-Hansen, M.; Nylandsted, J.; Jaattela, M., Vincristine induces dramatic lysosomal changes and sensitizes cancer cells to lysosome-destabilizing siramesine. Cancer Res.2007,67(5):2217-2225.
152. Parry, M. J.; Alakoskela, J. M. I.; Khandelia, H.; Kumar, S. A.; Jaattela, M.; Mahalka, A. K.; Kinnunen, P. K. J., High-affinity small molecule-phospholipid complex formation: Binding of siramesine to phosphatidic acid. J. Am. Chem. Soc.2008,130(39):12953-12960.
153. Ostenfeld, M. S.; Hoyer-Hansen, M; Bastholm, L.; Fehrenbacher, N.; Olsen, O. D.; Groth-Pedersen, L.; Puustinen, P.; Kirkegaard-Sorensen, T.; Nylandsted, J.; Farkas, T. Jaattela, M., Anti-cancer agent siramesine is a lysosomotropic detergent that induces cytoprotective autophagosome accumulation. Autophagy 2008,4(4):487-499.
154. Tao, Z. F.; Wang, L.; Stewart, K. D.; Chen, Z. H.; Gu, W.; Bui, M. H.; Merta, P.; Zhang, H. Y.; Kovar, P.; Johnson, E.; Park, C.; Judge, R.; Rosenberg, S.; Sowin, T.; Lin, N. H., Structure-based design, synthesis, and biological evaluation of potent and selective macrocyclic checkpoint kinase 1 inhibitors. J. Med. Chem.2007,50(7):1514-1527.
155. Ingrassia, L.; Lefranc, F.; Kiss, R.; Mijatovic, T., Naphthalimides and Azonafides as Promising Anti-Cancer Agents. Curr. Med. Chem.2009,16(10):1192-1213.
156. Ratain, M. J.; Mick, R.; Berezin, F.; Janisch, L.; Schilsky, R. L.; Vogelzang, N. J.; Lane, L. B., Phase I study of amonafide dosing based on acetylator phenotype. Cancer Res.1993, 53(10):2304-2308.
157. Brana, M. F.; Cacho, M.; Garcia, M. A.; de Pascual-Teresa, B.; Ramos, A.; Dominguez, M. T.; Pozuelo, J. M.; Abradelo, C.; Rey-Stolle, M. F.; Yuste, M.; Banez-Coronel, M.; Lacal, J. C, New analogues of amonafide and elinafide, containing aromatic heterocycles:Synthesis, antitumor activity, molecular modeling, and DNA binding properties. J. Med. Chem.2004, 47(6):1391-1399.
158. Antonini, I.; Santoni, G.; Lucciarini, R.; Amantini, C.; Sparapani, S.; Magnano, A., Synthesis and biological evaluation of new asymmetrical bisintercalators as potential antitumor drugs. J. Med. Chem.2006,49(24):7198-7207.
159. Van Quaquebeke, E.; Mahieu, T.; Dumont, P.; Dewelle, J.; Ribaucour, F.; Simon, G.; Sauvage, S.; Gaussin, J. F.; Tuti, J.; El Yazidi, M.; Van Vynckt, F.; Mijatovic, T.; Lefranc, F.; Darro, F.; Kiss, R.,2,2,2-Trichloro-N-({2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin5-yl}carbamoyl)acetamide (UNBS3157), a novel nonhematotoxic naphthalimide derivative with potent antitumor activity. J. Med. Chem.2007, 50(17):4122-4134.
160. Tumiatti, V.; Milelli, A.; Minarini, A.; Rosini, M.; Bolognesi, M. L.; Micco, M.; Andrisano, V.; Bartolini, M.; Mancini, R; Recanatini, M.; Cavalli, A.; Melchiorre, C., Structure-Activity Relationships of Acetylcholinesterase Noncovalent Inhibitors Based on a Polyamine Backbone.4. Further Investigation on the Inner Spacer. J. Med. Chem.2008, 51(22):7308-7312.
161. Norton, J. T.; Witsch, M. A.; Luong, L.; Kawamura, A.; Ghosh, S.; Stack, M. S.; Sim, E.; Avram, M. J.; Appella, D. H.; Huang, S., Synthesis and anticancer activities of 6-amino amonafide derivatives. Anti-Cancer Drugs 2008,19(1):23-36.
162. Iranpoor, N.; Firouzabadi, H.; Aghapour, G.; Vaezzadeh, A. R., Triphenylphosphine /2,3-dichloro-5,6-dicyanobenzoquinone as a new, selective and neutral system for the facile conversion of alcohols, thiols and selenols to alkyl halides in the presence of halide ions. Tetrahedron 2002,58(43):8689-8693.
163. Xuhong, Q.; Zhenghua, Z.; Kongchang, C., A study on the Ullmann Condensation Reaction of 4-chloro-1,8-naphthalic anhydride with N, N-dimethylformamide. J. Prakt. Chem. /Chem-Ztg 1992,334(2):161-164.
164. Zhang, Z. C; Yang, Y. Y.; Zhang, D. N.; Wang, Y. Y.; Qian, X. H.; Liu, F. Y, Acenaphtho[1,2-b]pyrrole derivatives as new family of intercalators:Various DNA binding geometry and interesting antitumor capacity. Biorg. Med. Chem.2006,14(20):6962-6970.
165. Mizushima, T.; Natori, S.; Sekimizu, K., Relaxation of supercoiled DNA associated with induction of heat shock proteins in Escherichia coli. Mol. Gen. Genet.1993,238(1-2):1-5.
166. Wang, J. C, Cellular roles of DNA topoisomerases:A molecular perspective. Nat. Rev. Mol. CellBiol.2002,3(6):430-440.
167. Li, T. K.; Liu, L. F., Tumor cell death induced by topoisomerase-targeting drugs. Annu. Rev. Pharmacol. Toxicol.2001,41:53-77.
168. Larsen, A. K.; Eseargueil, A. E.; Skladanowski, A., Catalytic topoisomerase II inhibitors in cancer therapy. Pharmacol. Then 2003,99(2):167-181.
169. Tanabe, K.; Ikegami, Y; Ishida, R.; Andoh, T., Inhibition of Topoisomerase-II by antitumor agents bis(2,6-dioxopiperazine) derivatives. Cancer Res.1991,51(18):4903-4908.
170. Zdolsek, J. M.; Olsson, G. M.; Brunk, U. T., Photooxidative damage to lysosomes of cultured macrophages by acridine orange. Photochem. Photobiol.1990,51(1):67-76.
171. Yuan, X. M.; Li, W; Dalen, H.; Lotem, J.; Kama, R.; Sachs, L.; Brunk, U. T., Lysosomal destabilization in p53-induced apoptosis. Proc. Natl. Acad. Set U. S. A.2002,99(9): 6286-6291.
172. Green, D. R.; Reed, J. C., Mitochondria and apoptosis. Science 1998,281(5381): 1309-1312.
173. Garrido, C; Galluzzi, L.; Brunet, M.; Puig, P. E.; Didelot, C.; Kroemer, G., Mechanisms of cytochrome c release from mitochondria. Cell Death Differ. 2006,13(9):1423-1433.
174. Lim, M. L. R.; Chen, B. H.; Beart, P. M.; Nagley, P., Relative timing of redistribution of cytochrome c and Smac/DIABLO from mitochondria during apoptosis assessed by double immunocytochemistry on mammalian cells. Exp. Cell Res.2006,312(7):1174-1184.
175. Vermes, I.; Haanen, C; Steffensnakken, H.; Reutelingsperger, C., A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labeled Annexin V. J. Immunol. Methods 1995,184(1):39-51.
176. Riccardi, C.; Nicoletti, I., Analysis of apoptosis by propidium iodide staining and flow cytometry. Nature Protocols 2006,1:1458-1461.
177. Zhang, W. T.; Ruan, J. L.; Wu, P. F.; Jiang, F. C.; Zhang, L. N.; Fang, W.; Chen, X. L. Wang, Y.; Cao, B. S.; Chen, G. Y.; Zhu, Y. J.; Gu, J.; Chen, J. G, Design, Synthesis, and Cytoprotective Effect of 2-Aminothiazole Analogues as Potent Poly (ADP-Ribose) Polymerase-1 Inhibitors. J. Med. Chem.2009,52(3):718-725.
178. Joo, S. S.; Yoo, Y. M., Melatonin induces apoptotic death in LNCaP cells via p38 and JNK pathways:therapeutic implications for prostate cancer. J. Pineal Res.2009,47(1):8-14.