摘要
恶性肿瘤严重威胁人类健康,已逐渐取代心脑血管疾病成为全球头号杀手。目前临床上常用的抗肿瘤药物普遍存在对实体瘤疗效较差、毒副作用大、容易产生多药耐药性等缺点。因此,研究疗效好,副作用小的抗肿瘤药物仍然是新药研究的热点之一。
抗肿瘤药物的作用靶点有许多,如拓扑异构酶I,蛋白激酶C和细胞周期蛋白依赖性激酶等。蛋白激酶C(PKC)是一大类磷脂依赖的丝/苏氨酸激酶,它在细胞的增殖调控、恶性转化以及癌变过程中起重要作用,是抗肿瘤药物设计的一个重要靶点。目前已有多个PKC抑制剂如UCN-01,CGP 41251和Enzastaurin作为抗肿瘤药物已进入临床试验。据文献报道,双吲哚马来酰亚胺类化合物具有显著的PKC抑制活性。为了获得具有更强的PKC抑制活性和抗肿瘤活性的新化合物,本文以双吲哚马来酰亚胺类化合物为先导化合物,对其进行结构改造,共合成了四类86个具有全新结构的二氮杂芳基马来酰亚胺类化合物,其中包括51个7-氮杂吲唑-吲哚马来酰亚胺类化合物,17个4-氮杂吲哚-吲哚-马来酰亚胺类化合物,8个3-(吡咯-3-基)-4-芳基马来酰亚胺类化合物和10个3-氯-4-吲哚马来酰亚胺类化合物,并对它们进行了体外抗肿瘤活性筛选。结果表明,7-氮杂吲唑-吲哚-马来酰亚胺类化合物和3-氯-4-吲哚马来酰亚胺类化合物与4-氮杂吲哚-吲哚-马来酰亚胺类化合物和3-(吡咯3-基)-4-芳基马来酰亚胺类化合物相比显示了较强的抗肿瘤活性。进而我们选择了部分代表性的化合物进行了初步的抗肿瘤机制的研究,结果表明:受试的大部分化合物显示了中等强度的PKC抑制活性,但活性顺序与它们的抗肿瘤活性并不一致,说明化合物除了PKC抑制作用,可能存在着其它作用机制。对代表性化合物a-14的进一步研究表明,促进肿瘤细胞的凋亡是其具有抗肿瘤活性的另一作用机制。
糖原合成酶-3p(GSK-3p)是双吲哚马来酰亚胺类化合物的另一个重要的作用靶点。GSK-3B在非胰岛素依赖型糖尿病(NIDDM)中,其活性会异常升高,从而抑制细胞糖原合成酶活性,降低细胞糖原合成水平。GSK-3β在阿尔茨海默尔氏病中,会导致Tau蛋白过度磷酸化,引起神经元纤维缠结。GSK-3β抑制剂对糖尿病和阿尔茨海默尔氏病(AD)的治疗都有重要的价值。本文对前期合成的部分二氮杂芳基马来酰亚胺类化合物进行了GSK-3β抑制活性的测试,并根据初步的构效关系进一步设计合成了16个结构全新的二氮杂芳基马来酰亚胺类化合物。结果表明,7-氮杂吲唑-吲哚-马来酰亚胺类化合物,4-氮杂吲哚-吲哚-马来酰亚胺类化合物和3-(吡咯-3-基)-4-芳基马来酰亚胺类化合物中的大部分化合物均显示了很强的GSK-3β抑制活性。其中部分化合物a-36,a-38～a-40,a-49,a-50,b-18,b-23,c-2和c-3能够显著的减少A-beta淀粉样蛋白诱发神经元tau蛋白的过度磷酸化,在细胞水平显示了GSK-3B的抑制活性。
As a significant health concern to human beings, cancer may soon displaced cardiovascular diseases as the leading killer. Although great efforts have been devoted to the discovery of anticancer agent, even the most widely used anticancer agents bear drawbacks, such as low efficacy against solid tumors, high toxicity, and development of multidrug resistance. Thus, research on anti-tumor drugs with higher efficacy, lower toxicity and minimum side effects has been a hotspot in the field of drug discovery.
Various targets including topoismerase I, protein kinase C and Cyclin-dependent Kinase have been validated for cancer chemotherapy. Among them, protein kinase C (PKC), a family of serine/threonine kinases, is regarded as a suitable target in anticancer drug design for its close connection with neoplasias. PKC inhibitors such as UCN-01, CGP 41251 and Enzastaurin are in clinical trials for their potential role in cancer therapy. Bisindolylmaleimides were reported to exhibit remarkable PKC inhibition. In this paper, we designed and synthesized 86 novel bisazaarylmaleimides, which could be group into four series: 51 7-azaindazole-indole-maleimides, 17 4-azaindole-indole-maleimides, 8 3-(pyrolle-3-yl)-4-arymaleimides and 10 3-chloro-4-indolemaleimides, in an attempt to discover novel PKC inhibitors with improved activity. All 86 synthesized compounds were tested for their in vitro antiproliferative activities against several human tumor cell lines, the result of which showed that 7-azaindazole-indole-maleimides and 3-chloro-4-indolemaleimides exhibited more potent antiproliferative activity than 4-azaindole-indole-maleimides and 3-(pyrolle-3-yl )-4-arymaleimides. Other biological evaluation studies involving some representive compounds were conducted to probe the mechanisms of these compounds. The fact that moderate PKC inhibitory activity for most tested compounds were observed was not consistent with the result of antiproliferative activity against human cancer cell lines, indicating that the tested compounds might have other mechanism against human cancer cell lines besides PKC inhibition. Further mechanism studies revealed that the antiproliferative activity of compound a-14 in tumor cells might be explained by its connection with the mitochondria-mediated apoptosis pathway.
GSK-3βis another target for bisindolylmaleimides. The high level of GSK-3βin NIDDM inhibits the activity of glycogen synthase kinase. GSK-3βleads to hyperphosphorylation of Tau protein, inducing neurofibrillary tanglesn. Thus, GSK-3βinhibitors are valuable agents for the treatment of diabetes and Alzerheim's Disease. Guided by the GSK-3B inhibitorary activity tests on some bisazaarylmaleimides synthesized in the preliminary phase, 16 novel inhibitors were designed based on preliminary QSAR information. The results showed that most 7-azaindazole-indole-maleimides, 4-azaindole-indole-maleimides and 3-(pyrolle-3-y 1 )-4-arymaleimides exhibited potent inhibitory activity against GSK-3β, among which compounds a-36, a-38～a-40, a-49, a-50, b-18, b-23, c-2 and c-3 significantly reduced Aβ-induced Tau hyperphosphorylation, demonstrating GSK-3βinhibitory activity at cell level.
引文
1.Omura,S.;Iwai,Y.;Hirano,A.;Nakagawa,A.;Awaya,J.;Tsuchiya,H.;Takahashi,Y.;Matsuma,R.Fermentation,isolation and preliminary characterization.J.Antibiot.1977,30,275-282.
2.Nettleton,D.E.;Doyle,T.W.;Krishnan,B.;Matsumoto,G.K.;Clardy,J.Isolation and structure of rebeccamycin - a new antitumor antibiotic from nocardia aerocoligenes.Tetrahedron Lett.1985,26,4011-4014.
3.Bush,J.A.;Long,B.H.;Catino,J.J.;Bradner,W.T.;Tomita,K.Production and biological activity of rebeccamycin,a novel antitumor agent.J.Antibiot.1987,40,668-678.
4.Long,B.H.;Rose,W.C.;Vyas,D.M.;Matson,J.A.;Forenza,S.Discovery of antitumor indolocarbazoles:rebeccamycin,NSC 655649,and fluoroindolocarbazoles.Curr.Med.Chem.-Anti-cancer agents.2002,255-266.
5.Prudhomme,M.Rebeccamycin analogues as anticancer agents.Eur.J.Med.Chem.2003,38,123-140.
6.Davis,P.D.;Hill,C.H.;Lawton,G.;Nixon,J.S.;Wilkinson,S.E.;Hurst,S.A.;Keech,E.;Turner,S.E.Inhibitors of Protein Kinase C.1.~1 2,3-Bisarylmaleimides.J.Med.Chem.1992,35,177-184.
7.Hers,I.;Tavare,J.M.;Denton,R.M.(Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity.FEBS Lett.1999,460,433-436.
8.Newton,A.C.Protein Kinase C:Structure,Function,and Regulation.J.Biol.Chem.1995,270,28495-28498.
9.Way,K.J.;Chou,E.;King,G.L.Trends Pharmacol Sci.2000,21,182-187.
10.Hoffmann,J.The potential for isoenzyme-selective modulation of protein kinase C.FASEB J.1997,11,649-669.
11.Mellor,H.;Parker,P.J.The extended protein kinase C superfamily.Biochem.J.1998,332,281-292.
12.Way,K.J.;Chou,E.;King,G.L.;Identification of PKC-isoform-specific biological actions using pharmcological approaches.Tips.2000,21,181-187.
13.Kanzawa,F.;Nishio,K.;Kubota,N.;Saijo,N.New Indolocarbazole Substance,NB-506,and Establishment of NB-506-resistant Cell Lines,SBC-3/NB~1.Cancer Res.1995,55,2806-2813.
14.Komatani,H.;Kotani,H.;Hara,Y.;Nakagawa,R.;Matsumoto,M.;Arakawa,H.;Nishimura,S.Specific,ATP-binding Cassette Transporter as a Transporter of NB-506 and J-107088,Topoisomerase I Inhibitors with an Indolocarbazole Structure.Cancer Res.2001,61,2827-2832.
15.Akinaga,S.;Sugiyama,K.;Akiyama,T.UCN-01(7-hydroxystaurosporine) and other indolocarbazole compounds:a new generation of anti-cancer agents for the new century? Anti-cancer Drug Des.2000,15,43-52.
16.Meyer,T.;Regenass,U.;Fabbro,D.;Alteri,E.;R(o|¨)sel,J.;Müller,M.;Caravatti,G.;Matter,A.A derivative of staurosporine(CGP 41251) shows selectivity for protein kinase C inhibition and in vitro anti-proliferative as well as in vivo anti-tumor activity.Int.J.Cancer 1989,43,851-856.
17.Faul,M.M.;Gillig,J.R.;Jirousek,M.R.;Ballas,L.M.;Schotten,T.;Kahl,A.;Mohr,M.Acylic N-(azacycloalkyl)bisindolemaleimides:isozyme selective PKCβ inhibitors.Bioorg.Med.Chem.Lett.2003,13,1857-1859.
18.Embi,N.;Rylatt,D.B.;Cohen,P.Glycogen synthase kinase-3 from rabbit skeletal muscleSeparation from cyclic-AMP-dependant protein kinase and phosphorylase kinase.Eur.J.Biochem.1980,107,519-527.
19.Harwood,A.Regulation of GSK-3,a cellular multiprocessor.J.Cell.2001,105,821-824.
20.Wagman,A.S.;Nuss,J.M.Current therapies and emerging targets for the treatment of diabetes.Curr.Pharm.Des.2001,7,417-450.
21.Castro,A.;Martinez,A.Inhibition of tau phosphorylation:A new therapeutical strategy for the treatment of Alzheimer's disease and other neurodegenerative disorders.Exp.Opin.Ther.Pat.2000,10,1519-1527.
22.Steinbrecher,K.A;Wilson,W3rd;Cogswell,P.C;Baldwin,A.S.Glycogen synthase kinase 3βfuctions to specify gene-specific,NF-κB-dependent transcription Steinbrecher.Mol.Cell.Biol,2005,25,8442-8455.
23.Tanaka,M.;Sagawa,S.;Hoshi,J.;Shimoma,F.;Matsuda,I.;Sakoda,K.;Sasase,T.;Shindo,M.; Inaba, T. Synthesis of anilino-monoindolylmaleimides as potent and selective PKCP inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5171-5174.
24. Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.; Hurst, S. A.; Keech, E.; Kumar, M. K. H.; Lawton, G.; Nixon, J. S.; Wilkinson. S. E. Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity. J. Med. Chem. 1992, 35, 994-1001.
25. Zhang, H.-C.; Derian, C. K.; McComsey, D. F.; White, K. B.; Ye, H.; Hecker, L. R.; Li, J.; Addo, M. F.; Croll, D.; Eckardt, A. J.; Smith, C. E.; Li, Q.; Cheung, W.-M.; Conway, B. R.; Emanuel, S.; Demarest, K. T.; Andrade-Gordon, P.; Damiano, B. P.; Maryanoff, B. E. Novel Indolylindazolylmaleimides as Inhibitors of Protein Kinase C-P: Synthesis, Biological Activity, and Cardiovascular Safety. J. Med. Chem. 2005, 48, 1725-1728.
26. Xu, G. Q.; Zhang, C.; Zhang, L.; Zhou, X. L.; Yang, B.; He, Q. J.; Hu, Y. Z. Synthesis, cytotoxi-city and protein kinase C inhibition of arylpyrrolylmaleimides. Archiv der Pharmazie, 341, 273-280.
27. Bertrand, J. A.; Thieffine, S.; Vulpettil, A.; Cristiani, C.; Valsasina, B.; Knapp, S.; Kalisz, H. M.; Flocco, M. Structural Characterization of the GSK-3β Active Site Using Selective and Non-selective ATP-mimetic Inhibitors. J. Mol. Biol. 2003, 333, 393-407.
28. Faul, M. M.; Winneroski, L. L.; Krumrich, C. A. A New, Efficient Method for the Synthesis of Bisindolylmaleimides. J. Org. Chem. 1998, 63, 6053-6058.
29. Sanchez-Martinez, C.; Shih, C.; Zhu, G.; Li, T.; Brooks, H. B.; Patel, B. K. R.; Schultz, R. M.; DeHahn, T. B.; Spencer, C. D.; Watkins, S. A.; Ogg, C. A.; Considine, E.; Dempsey, J. A.; Zhang, F.; Studies on cyclin-dependent kinase inhibitors: indolo-[2,3-a]pyrrolo[3,4-c]carbazoles versus bis-indolylmaleimides. Bioorg. Med. Chem. Lett. 2003, 13, 3841-3846.
30. Roy, S.; Gribble, G. W. A Practical Method for the Synthesis of Indolylaryl- and Bisindolylmaleimides. Org. Lett. 2006, 8, 4975-4977.
31. Routier, S.; Coudert, G.; Merour, J.-Y. Synthesis of naphthopyrrolo [3, 4-c]carbazoles. Synthesis, 1995,12,1511-1516;
32. Zhang, H.-C.; Maryanoff, B.; Conway, B.; White, K.; Ye, H.; Hecker, L. R.; McComsey, D. F.; WO 2002046183, 2003.
33. Zhang, H.-C.; Kho, G. H.; Maryanoff, B. E.; Ye, H.; Shen, L. WO 2003095452, 2003.
34. Lynch, B. M.; Khan, M. A.; Teo, H. C.; Pedrotti, F. Pyrazolo[3,4-b]: Syntheses, reactions, and nuclear magnetic resonance spectra. Can. J. Chem. 1988, 66, 420-428.
35. Kocevar, M.; Stanovnik, B.; Tisler, M. J. Heterocycl. Chem. 1978, 15, 1175-1184.
36. Zhang, H.-C.; Maryanoff, B.; Conway, B.; White, K.; Ye, H.; Hecker, L. R.; McComsey, D. F.; WO 2002046183, 2003.
37. Ohkubo, M.; Nishimura, T.; Jona, H.; Honma, T. Morishima, H. Practical synthesis of indolopyrrolocarbazoles. Tetrahedron 1996, 52, 8099-8112.
38. Brenner, M.; Rexhausen, H.; Steffan, B.; Steglich, W. Synthesis of arcyriarubin b and related bisindolylmaleimides. Tetrahedron 1988, 2887-2892.
39. Cash, M. T.; Schreiner, P. R.; Phillips, R. S. Excited state tautomerization of azaindole. Org. Biomol. Chem. 2005, 3, 3701-3706.
40. Relies, H. M. Organic chemistry in thionyl chloride. I. Dichloromaleimide chemistry. II. Thionyl chloride-pyridine method for the conversion of maleimides to dichloromaleimides. J. Org. Chem. 1972, 37, 3630-3637.
41.Gallant, M.; Link, J.T.;Danishefsky, S.J. A stereoselective synthesis of indole- .beta.-N-glycosides: an application to the synthesis of rebeccamycin. J. Org. Chem. 1993, 58, 343-349.
42. outier, S.; Ayerbe, N.; Merour, J. Y.; Coudert, G.; Bailly, C.; Pierre, A.; Pfeiffer, B.; Caignardd, D. H.; Renard, P. Synthesis and biological evaluation of 7-azaindolocarbazoles. Tetrahedron 2002, 58, 6621-6630.
43. Zhang, H.-C.; Ye, H.; Conway, B. R.; Derian, C. K.; Addo, M. F.; Kuo, G. H.; Hecker, L. R.; Croll, D. R.; Li, J.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Andrade-Gordon, P.; Damiano, B. P.; Maryanoff, B. E. 3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3. Bioorg. Med. Chem. Lett. 2004, 14, 3245-3250.
44. Zhang, Z. X.; Yang, Z.; Wong, H.; Zhu, J. L.; Meanwell, N. A.; Kadow, J. R; Wang, T. An Effective Procedure for the Acylation of Azaindoles at C-3. J. Org. Chem. 2002, 67, 6226-6227.
45.Neill,D.J.;Shen,L.;Prouty,C;Conway,B.R.;Westover,L.;Xu,J.Z.;Zhang,H.-C;Maryanoff,B.E.;Murray,W.V.;Demarest,K.T.;Kuoa,G.H.Design,synthesis,and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase-3β(GSK-3β) inhibitors.Bioorg.Med.Chem.2004,12,3167-3185.
46.Muchowski,J.M.;Solas,D.R.β-substituted pyrroles via electrophilic substation of n-triisopropylsilylpyrrole.Tetrahedron lett.1983,24,3455-3456.
47.McDonald,R.N.;Krueger,R.A.The Catalyzed Reaction of Acetylenedicarboxylic Acid and Thionyl Chloride.J.Org.Chem.1963,28,2542-2544
48.陈红飙,林原斌,段福长.N-芳基马来酰亚胺的合成与表征.湘潭大学自然科学学报,1998,20,81-83.
49 Marijan,K.;Branko,S.;Miha,T.The Semmler-Wolff aromatization and Schmidt reaction applied to some pyrido[2',3':3,4]pyrazolo[5,1-c][1,2,4]benzotriazines.Monatshefte fuer Chemie.1988,119,597-603.
50.Rafael,F.;Carmen,G;Pere,V.SRN1 reaction.Synthetic application to 4-azaindoles.Heterocycles 1981,16,1473-1474.
1. Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y.; Matsuma, R. Fermentation, isolation and preliminary characterization. J. Antibiot. 1977, 30, 275-282.
2. Bush, J. A.; Long, B. H.; Catino, J. J.; Bradner, W. T.; Tomita, K. Production and biological activity of rebeccamycin, a novel antitumor agent. J. Antibiot. 1987, 40, 668-678.
3. Carrasco, C.; Vezin, H.; Wilson, W. D.; Ren, J.; Chaires, J. B.; Bailly, C. DNA binding properties of the indolocarbazole antitumor drug NB-506. Anticancer Drug Des. 2001, 16, 99-107.
4. Prudhomme, M. Rebeccamycin analogus as anti-cancer agents. Eur. J. Med. Chem. 2003, 38, 123-140.
5. Newton, A. C. Protein Kinase C: Structure, Function, and Regulation. J. Biol. Chem. 1995, 270, 28495-28498.
6. Way, K. J.; Chou, E.; King, G. L. Trends Pharmacol Sci. 2000, 21, 182-187.
7. Hoffmann, J. The potential for isoenzyme-selective modulation of protein kinase C. FASEB J. 1997,11,649-669.
8. Mellor, H.; Parker, P. J. The extended protein kinase C superfamily. Biochem. J. 1998, 332, 281-292.
9. Sasase T. PKC - a target for treating diabetic complications. Drugs Fut. 2006, 31, 503-511.
10. Serova, M.; Ghoul, A.; Benhadji, K. A. Semi. Oncol. 2006, 33, 466-478.
11. Mackay, H. J.; Twelves, C. J.; Protein kinase C: a target for anticancer drugs. Endocr. -relat. Cancer, 2003, 10, 389-396.
12. Nguyen, T.; Ogbi, M.; Guo, D. H.; Johnson, A. J. Modulation of Mitochondrial Protein Kinase C Isozymes: A New Therapeutic Frontier? Curr. Enzyme Inhibition. 2007, 3, 143-159.
13. Tamaoki, T.; Nomoto, H.; Takahashi, I.; Kato, Y.; Morimoto, M.; Tomita, F. Staurosporine, a potent inhibitor of phospholipid/Ca++ dependent protein kinase. Biochem. Biophysic. Res. Commun. 1986, 135, 397-402.
14. Vegesna, R.V.; Wu, H. L.; Mong, S.; Crooke, S. T. Staurosporine inhibits protein kinase C and prevents phorbol ester- mediated leukotriene D4 receptor desensitization in RBL-1 cells. Mol. pharmacol. 1988, 33, 537-542.
15. Hu H. DDT. 1996, 1,438-447.
16. Gescher, A. Staurosporine analogues: Pharmacological toys or useful antitumor agents? Crit. Rev. Oncol. Hematol. 2000, 34, 127-135.
17. Yoshikawa, N.; Nakamura, K.; Yamaguchi, Y.; Kagota, S.; Shinozuka, K.; Kunitomo, M. Effect of PKC412, a selective inhibitor of protein kinase C, on lung metatasis in mice injected with B16 melanoma cells. Life Science, 2003, 72,1377-1387.
18. Slater, M. J.; Cockerill, S.; Baxter, R.; Bonser, R. W.; Gohil, K.; Gowrie, C.; Robinson, J. E.; Littler, E.; Parry, N.; Randall, R.; Snowden, W. Indolocarbazoles: potent, selective inhibitors of human cytomegalovirus replication. Bioorg. Med. Chem. 1999, 7, 1067-1074.
19. Kleinschroth, J.; Hartenstein, J.; Rudolph, C.; Schachtele, C. Novel indolocarbazole protein kinase C inhibitors with improved biochemical and physicochemical properties. Bioorg. Med. Chem. Lett, 1995, 5, 55-60.
20. Martiny-Baron, G.; Kazanietz, M. G.; Mischak, H.; Blumberg, P. M; Kochs, G.; Hug, H.; Marme, D.; Schatchtele, C. Selective inhibition of protein-kinase-C isozymes by the indolocarbazole Go 6976. J. Bio. Chem. 1993, 268, 9194-9197.
21. Vice, S. F.; Bishop, W. R.; McCombie, S. W. Dao, H.; Frank, E.; Ganguly, A. K. Indolocarbazole nitrogens linked by three-atom bridges: a potent new class of PKC inhibitors. Bioorg. Med. Chem. Lett. 1994, 4, 1333-1338.
22. Davis, P. D.; Hill, C. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E.; Hurst, S. A.; Keech, E.; Turner, S. E. Inhibitors of Protein Kinase C. 1.~1 2,3-Bisarylmaleimides. J. Med. Chem. 1992, 35, 177-184.
23. Meyer, T.; Reaanass, U.; Fabbro, D. int. J. Cancer. 1989, 43, 852-856.
24. Osada, H.; Takahashi, H.; Tsunoda, H.; Kusakabe, K. I. A new inhibitor of protein kinase C, RK-286C (4'-demethylamino-4'-hydroxystaurosporine). I. Screening, taxonomy, fermentation and biological activity. J. Antibiotics. 1990, 43, 163-167.
25. Gross, J. L.; Herblin, W.; Do, U. H.; Pounds, J. S.; Buenaga, L. J.; Stephens, L. E. Characterization of specific (3H) dimethylstaurosporine binding to protein kinase C. Biochem. Pharmacol. 1990, 40, 343-350.
26. Davis, P. D.; Elliott, L. H.; Harris, W.; Hill, C. H.; Hurst, S. A.; Keech, E.; Kumar, M. K. H.; Lawton, G.; Nixon, J. S.; Wilkinson, S. E. Inhibitors of protein kinase C. 2. Substituted bisindolylmaleimides with improved potency and selectivity. J. Med. Chem. 1992, 35, 994-1001.
27 Faul, M. M.; Gillig, J. R.; Jirousek, M.; Ballas, L. M.; Schotten, T.; Kahl, A.; Mohr, M. Acyclic N-(azacycloalkyl)bisindolylmaleimides: isozyme selective inhibitors of PKCp. Bioorg. Med. Chem. Lett. 2003, 13, 1857-1859.
28. Jirousek, M. R.; Gillig, J. R.; Gonzalez, C. M.; Heath, W. F.; McDonald III, J. H.; Neel, D. A.; Rito, C. J.; Singh, U.; Stramm, L. E.; Melikian-Badalian, A.; Baevsky, M.; Ballas, L. M.; Hall, S. E.; Winneroski, L. L.; Faul, M. M. (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro -4,9:16,21 -dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecene- 1,3(2H) -dione (LY333531) and Related Analogues: Isozyme Selective Inhibitors of Protein Kinase Cβ . J. Med. Chem. 1996, 39, 2664-2671.
29. Anon, N. L. Ruboxistaurin: LY 333531. Drugs in R&D. 2007, 8, 193-199.
30. Zhang, H.-C.; White, K. B.; Ye, H.; McComsey, D. F.; Derian, C. K.; Addo, M. F.; Andrade-Gordon, P.; Eckardt, A. J.; Conway, B. R.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Emanuel, S.; Maryanoff, B. E. Macrocyclic bisindolylmaleimides as inhibitors of protein kinase C and glycogen synthase kinase-3. Bioorg. Med. Chem. Lett. 2003, 13, 3049-3053.
31. Grodsky, N.; Li, Y.; Bouzida, D. Structure of the Catalytic Domain of Human Protein Kinase C beta II Complexed with a Bisindolylmaleimide Inhibitor. Biochem. 2006,45, 13970-13981.
32. Hendricks, R. T.; Sherman, D.; Strnlovicil, B.; Broka, C. A. 2-aryl-indolyl maleimides - novel and potent inhibitors of protein kinase C. Bioorg. Med. Chem. Lett. 1995, 5, 67-72.
33. Tanaka, M.; Sagawa, S.; Hoshi, J.; Shimoma, F. Matsuda, I.; Sakoda, K.; Sasase, T.; Shindo, M.; Inaba, T. Synthesis of anilino-monoindolylmaleimides as potent and selective PKCP inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 5171-5174.
34. Tanaka, M.; Sagawa, S.; Hoshi, J.-I. Shimoma, F.; Yasue, K.; Ubukata, M.; Ikemoto, T.; Hase, Y. Takahashi, M. Sasase, T.; Ueda, N.; Matsushita, M.; Inaba, T. Synthesis, SAR studies, and pharmacological evaluation of 3-anilino-4-(3-indolyl) maleimides with conformationally restricted structure as orally bioavailable PKCβ-selective inhibitors. Bioorg. Med. Chem. 2006, 14, 5781-5794.
35. Zhang, H.-C.; Derian, C. K.; McComsey, D. F.; White, K. B.; Ye, H.; Hecker, L. R.; Li, J.; Addo, M. F.; Croll, D.; Eckardt, A. J.; Smith, C. E.; Li, Q.; Cheung, W.-M; Conway, B. R.; Emanuel, S.; Demarest, K. T.; Andrade-Gordon, P.; Damiano, B. P.; Maryanoff, B. E. Novel Indolylindazolylmaleimides as Inhibitors of Protein Kinase C-β: Synthesis, Biological Activity, and Cardiovascular Safety. J. Med. Chem. 2005, 48, 1725-1728.
36. Xu, G. Q.; Zhang, C.; Zhang, L.; Zhou, X. L.; Yang, B.; He, Q. J.; Hu, Y. Z. Synthesis, cytotoxi-city and protein kinase C inhibition of arylpyrrolylmaleimides. Archiv der Pharmazie, 2008, 341, 273-280.
37. He, M.; Buisine, E.; Tartar, A. Sergheraert, C. Design and synthesis of new leads for PKC bisubstrate inhibitors. Bioorg. Med. Chem. Lett. 1994, 4, 2845-2850.
38. Von Matt, P.; Wagner, J. Indolylmaileimide derivatives. WO 2004072062, 2004.
39. Wagner, J.; Van Eis, M.; Von Matt, P.; Evenou, J. P. Schuler, W. Indolylmaileimide derivatives. WO 2007006533, 2007.
40. Brana, M. F.; Gradillas, A.; Ovalles, A. G.; Lopez, B.; Acero, N.; Llinares, F.; Mingarro, D. M. Synthesis and biological activity of N,N-dialkylaminoalkyl-substituted bisindolyl and diphenyl pyrazolone derivatives. Bioorg. Med. Chem. 2006, 14, 9-16.
41. Karabelas, K.; Lepisto, M.; Sjo, P. New dihydro[1,2,4]triazole derivatives useful as protein kinase C inhibitors. NZ 515281, 2003.
42. Steinbrecher, K. A; Wilson, W3rd; Cogswell P. C.; Baldwin, A. S. Glycogen synthase kinase 3β fuctions to specify gene-specific, NF-κB-dependent transcription Steinbrecher. Mol. Cell. Biol, 2005, 25, 8442-8455.
43. Ougolkov, A. V.; Billadeau, D. D. Future Oncol. 2006, 2, 92-100.
44. Hers, I.; Tavare, J. M.; Denton, R. M. The protein kinase C inhibitors bisindolylmaleimide I (GF 109203x) and IX (Ro 31-8220) are potent inhibitors of glycogen synthase kinase-3 activity. FEBS Lett. 1999,460,433-436.
45. Zhang, H.-C.; Bonaga, L. V. R.; Ye, H.; Derian, C. K.; Damiano, B. P.; Maryanoff, B. E. Novel bis (indolyl) maleimide pyridinophanes that are potent, selective inhibitors of glycogen synthase kinase-3. Bioorg. Med. Chem. Lett. 2007, 17, 2863-2868.
46. Kuo, G.-H.; Prouty, C.; DeAngelis, A.; Shen, L.; O'Neill, D. J.; Shah, C.; Connolly, P. J.; Murray, W. V.; Conway, B. R.; Cheung,P.; Westover, L.; Xu, J. Z.; Look, R. A.; Demarest, K. T.; Emanuel, S.; Middleton, S. A.; Jolliffe, L.; Beavers, M. P.; Chenet, X. Synthesis and Discovery of Macrocyclic Polyoxygenated Bis-7- azaindolylmaleimides as a Novel Series of Potent and Highly Selective Glycogen Synthase Kinase-3β Inhibitors. J. Med. Chem. 2003,46, 4021-4031.
47. Shen, L.; Prouty, C.; Conway, B. R.; Westover, L.; Xu, J. Z.; Look, R. A.; Chen, X.; Beavers, M. P.; Roberts, J.; Murray, W. V.; Demarest, K. T.; Kuo, G.-H. Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3β (GSK-3β) inhibitors. Bioorg. Med. Chem. 2004, 12, 1239-1255.
48. Bertrand, J. A.; Thieffine, S.; Vulpettil, A.; Cristiani, C.; Valsasina, B.; Knapp, S.; Kalisz, H. M.; Flocco, M. Structural Characterization of the GSK-3β Active Site Using Selective and Non-selective ATP-mimetic Inhibitors. J. Mol. Biol. 2003, 333, 393-407.
49. O'Neill, D. J.; Shen, L.; Prouty, C.; Conway, B. R.; Westover, L.; Xu, J. Z.; Zhang, H.-C.;Mary anoff, B.E.; Murray, W.V.; Demarest, K.T.; Kuo, G-H. Design, synthesis, and biological evaluation of novel 7-azaindolyl-heteroaryl-maleimides as potent and selective glycogen synthase kinase-3β (GSK-3β) inhibitors. Bioorg. Med. Chem. 2004, 12, 3167-3185.
50. Zhang, H.-C.; Ye, H.; Conway, B. R.; Derian, C. K.; Addo, M. F.; Kuo, G.-H.; Hecker, L. R.; Croll, D. R.; Li, J.; Westover, L.; Xu, J. Z.; Look, R.; Demarest, K. T.; Andrade-Gordon, P.; Damiano, B. P.; Maryanoffet, B. E. 3-(7-Azaindolyl)-4-arylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3. Bioorg. Med. Chem. Lett., 2004, 14, 3245-3250.
51. Wang, J. C. DNA Topoisomerases. Annu. Rev. Biochem. 1996, 65, 635-692.
52. Redinbo, M. R.; Stewart, L.; Kuhn, P.; Champoux, J. J.; Hoi, W. G. J. Crystal structures of human topoisomerase I in covalent and noncovalent complexs with DNA. Science 1998, 279, 1504-1513;
53. Stewart, L.; Redinbo, M. R.; Qiu, Y. ibid. 1998, 279, 1534.
54. Tsao, Y.-P.; Russo, A.; Nyamuswa, G.; Silber, R.; Liu, L. F. Interaction between Replication Forks and Topoisomerase I-DNA Cleavable Complexes: Studies in a Cell-free SV40 DNA Replication System. Cancer Res. 1993, 53, 5908-5914.
55. Pereira, E. R.; Belin, L.; Sancelme, M.; Prudhomme, M.; Oilier, M.; Rapp, M.; Severe, D.; Riou,J.-F.; Fabbro, D.; Meyer, T. Structure-Activity Relationships in a Series of Substituted Indolocarbazoles: Topoisomerase I and Protein Kinase C Inhibition and Antitumoral and Antimicrobial Properties J. Med. Chem. 1996, 39, 4471-4477.
56. Kaneko, T.; Wong, H.; Utzig, J.; Schuring, J.; Doyle, T. W. Water soluble derivatives of Rebecc-amycin. J. Antibiot. 1990,43, 125-127.
57. Anizon, F.; Belin, L.; Moreau, P.; Sancelme, M.; Voldoire, A.; Prudhomme, M.; Oilier, M.; Severe, D.; Riou, J.-F.; Bailly, C.; Fabbro, D.; Meyer, T. Syntheses and Biological Activities (Topoisomerase Inhibition and Antitumor and Antimicrobial Properties) of Rebeccamycin Analogues Bearing Modified Sugar Moieties and Substituted on the Imide Nitrogen with a Methyl Group. J. Med. Chem. 1997, 40, 3456-3465.
58. Prudhomme, M. Synthesis and biological activities of 7-azarebeccamycin analogues bearing the sugar moiety on the nitrogen of the pyridine ring. Curr. Med. Chem. 2000, 7, 1189-1212.
59. Long, B. H.; Rose, W. C.; Vyas, D. M. Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles. Curr. Med. Chem. Anticancer Agents. 2002, 2, 255-266.
60. Saulnier, M. G.; Balasubramanian, B. N.; Long, B. H.; Frennesson, D. B.; Ruediger, E.; Zimmermann, K.; Eummer, J. T.; Laurent, D. R. S.; Stoffan, K. M.; Naidu, B. N.; Mahler, M.; Beaulieu, F.; Bachand, C.; Lee, F. Y.; Fairchild, C. R.; Stadnick, L. K.; Rose, W. C.; Solomon, C.; Wong, H.; Mattel, A.; Wright, J. J.; Kramer, R.; Langley, D. R.; Vyas, D. M. Discovery of a Fluoroindolo[2,3-a]carbazole Clinical Candidate with Broad Spectrum Antitumor Activity in Preclinical Tumor Models Superior to the Marketed Oncology Drug, CPT-11. J. Med. Chem. 2005, 48,2258-2261.
61. Ohkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.; Morishima, Hajime. Synthesis of NB-506, a new anticancer agent. Tetrahedron, 1997, 53, 585-592.,
62. Kanzawa, F.; Nishio, K.; Kubota, N.; Saijo, N. Antitumor Activities of a New Indolocarbazole Substance, NB-506, and Establishment of NB-506-resistant Cell Lines, SBC-3/NB. Cancer Res. 1995,55,2806-2813.
63. Komatani, H.; Kotani, H.; Hara, Y.; Nakagawa, R.; Matsumoto, M.; Arakawa, H.; Nishimura, S. Identification of Breast Cancer Resistant Protein/Mitoxantrone Resistance/Placenta-Specific, ATP-binding Cassette Transporter as a Transporter of NB-506 and J-107088, Topoisomerase I Inhibitors with an Indolocarbazole Structure. Cancer Res. 2001, 61, 2827-2832.
64. Ohkubo, M.; Kojiri, K.; Kondo, H.; Tanaka, S.; Kawamoto, H.; Nishimura, T.; Nishimura, I.; Yoshinari, T.; Arakawa, H.; Suda, H.; Morishima, H.; Nishimura, S. Synthesis and biological activities of topoisomerase I inhibitors, 6-N-amino analogues of NB-506. Bioorg. Med. Chem. Lett. 1999,9, 1219-1224.
65. Yoshinari, T.; Ohkubo, M.; Fukasawa, K.; Egashira, S.-I.; Hara, Y.; Matsumoto, M.; Nakai, K.; Arakawa, H.; Morishima, H.; Nishimura, S. Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I. Cancer Res. 1999, 59, 4271-4275.
66. Goossens, J.-F.; Kluza, J.; Vezin, H.; Kouach, M.; Briand, G.; Baldeyrou, B.; Wattez, N.; Bailly, C. Plasma stability of two glycosyl indolocarbazole antitumor agents. Biochem. Pharmacol. 2003, 65,25-34. .
67. Arakawa, H.; Morita, M.; Kodera, T.; Okura, A.; Ohkubo, M.; Morishima, H.; Nishimura, S. In vivo Anti-tumor Activity of a Novel Indolocarbazole Compound, J-107088, on Murine and Human Tumors Transplanted into Mice. Jpn. J. Cancer Res. 1999, 90, 1163 -1170.
68. Cavazos, C. M.; Keir, S. T.; Yoshinari, T.; Bigner, D. D.; Friedman, H. S. Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N-(1-hydroxymethyl-2-hydroxy)ethylamino-12,13 -dihydro-13-(6-D-glucopyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)-dione]against pediatric and adult central nervous system tumor xenografts. Cancer Chemother. Pharmacol. 2001, 48, 250-254.
69. Giannis, A.; Huwe, A.; Mazitschek, R. Design of a Novel Class of Peptide Inhibitors of Cyclin-dependent Kinase/Cyclin Activation. Angew. Chem. Int. Ed. 2003, 42, 2122-2138.
70. Zhu, G. X.; Conner, S. E.; Zhou, X. Shih, C.; Li, T.; Anderson, B. D.; Brooks, H. B.; Campbell, R. M.; Considine, E.; Dempsey, J. A.; Faul, M. M.; Ogg, C.; Patel, B.; Schultz, R. M.; Spencer, C. D.; Teicher, B.; Watkins, S. A.; J. Med. Chem. 2003,46, 2027-2030.
71. Sanchez-Martinez, C.; Shih, C.; Zhu, G. X.; Paal, M.; Somoza, C.; Li, T.; Kumrich, C. A.; Winneroski, L. L.; Xun, Z.; Brooks, H. B.; Patel, B. K. R.; Schultz, R. M.; DeHahn, T. B.; Spencer, C. D.; Watkins, S. A.; Considine, E.; Dempsey, J. A.; Ogg, C. A.; Campbell, R. M. A.; nderson, B. A.; Wagner, J. Aryl[a]pyrrolo[3,4-c]carbazoles as selective cyclin D1-CDK4 inhibitors. Bioorg. Med. Chem. Lett. 2003, 13, 3835-3839.
72. Sanchez-Martinez, C.; Shih, C.; Zhu, G. X.; Li, T.; Brooks, H. B.; Patel, B. K. R.; Schultz, R. M.; DeHahn, T. B.; Spencer, C. D.; Watkins, S. A.; Ogg, C. A.; Considine, E.; Dempsey, J. A.; Zhang, F. Studies on cyclin-dependent kinase inhibitors: indolo-[2,3-a]pyrrolo[3,4-c]carbazoles versus bis-indolylmaleimides. Bioorg. Med. Chem. Lett. 2003, 13, 3841-3846.
73. Kaufmann, W. K.; Paules, R. S. DNA damage and cell cycle checkpoints. FASEB J. 1996, 10, 238-247.
74. Kastan, M. B.; Onyekwere, O.; Sidransky, D. Cancer Res. 1991, 51, 6302-6311.
75. Murray, A. W. Creative blocks: cell-cyle checkpoints and feed back controls. Nature (Lond.). 1992, 359, 599-604.
76. Weinert, T.; Lydall, D. Cell cycle checkpoints, genetic instability and cancer. Semin. Cancer Biol. 1993,4, 129-140.
77. Nurse, P. Checkpoint pathways come of age. Cell. 1997, 91, 865-867.
78. Kao, G. D.; McKenna, W. G.; Maity, A. Cyclin B1 availability is a rate-limiting component of the radiation-induced G2 delay in HeLa cells. Cancer Res. 1997, 57, 753-758.
79. Berlinck, R. G. S.; Britton, R.; Piers, E. Synthesis and Biological Activities of New Checkpoint Kinase 1 Inhibitors Structurally Related to Granulatimide. J. Org. Chem. 1998, 63, 9850-9856.
80. Roberge, M.; Berlinck, R. G. S.; Xu, L. ; Anderson, H. J.; Lim, L. Y.; Curman, D.; Stringer, C. M.;Freind,S.H.;Davies,P.;Vincent,I.;Haggarty,S.J.;Kelly,M.T.;Britton,R.;Piers,E.;Andersen,R.J.High-throughput assay for G2 checkpoint inhibitors and identification of the structurally novel compound isogranulatimide.Cancer Res.1998,58,5701-5706.
81.Zhao,B.G.;Bower,M.J.;McDevitt,P.J.;Zhao,H.Z.;Davis,S.T.;Johanson,K.O.;Green,S.M;Concha,N.O.;Zhou B.-B.S.Structural Basis for Chk1 Inhibition by UCN-01*.J.Biol.Chem.2002,277,46609-46615.
82.Sato,S.;Fujita,N.;Tsuruo,T.Interference with PDK1-Akt survival signaling pathway by UCN-01(7-hydroxystaurosporine).Oncogene.2002,21,1727-1738.
83.McGovern,S.;Shoichet,B.K.Kinase Inhibitors:Not Just for Kinases Anymore.J.Med.Chem.2003,46,1478-1483.
84.Tao,M.;Park,C.H;Bihovsky,R.Wells,G.J.;Husten,J.;Ator,M.A.;Hudkins,R.L.Synthesis and structure-activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors.Bioorg.Med.Chem.Lett.2006,16,938-942.
85.Yang,S.-M.;Malaviya,R.;Wilson,L.J.;Argentieri,R.;Chen,X.;Yang,C;Wang,B.;Cavender,D.;Murray,W.V.Simplified staurosporine analogs as potent JAK3 inhibitors.Bioorg.Med.Chem.Lett.2007,16,326-331.