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喜树碱工业化全合成及结构多样性改造
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摘要
肿瘤是一种常见的疾病,在发达国家,恶性肿瘤是仅次于心血管疾病的第二大健康杀手,而在我国农村则是致死率最高的疾病。因此,研究开发新型抗肿瘤药物是新药研发的热点之一。
     喜树碱类药物是目前临床使用的五大抗肿瘤药物之一,能专一性抑制拓扑异构酶Ⅰ,其衍生物伊立替康、拓扑替康、贝洛替康先后上市,另外还有许多喜树碱类药物正处于临床和临床前研究,因此,喜树碱的研究仍是目前抗肿瘤药物的热门领域。
     几十年来,国内外众多科学家们围绕着喜树碱的合成已经开发了许多成功的全合成路线,有的已经进行了工业化生产,但仍存在成本高,立体选择性不强等问题。而对于喜树碱新型衍生物的研究,虽然有许多新型衍生物进入不同的研究阶段,但其内酯E环不稳定还没有得到根本的解决。
     我们课题组在Comins方法的基础上,设计了一条全新的全合成路线,其以2-甲氧基烟酸为起始原料,通过手性诱导方法引入手性中心,以11步反应总收率23%完成了喜树碱的合成,其ee值达到100%,目前已经在齐鲁药业进行工业化。
     而且,在全合成的基础上,我们利用结构多样性全合成方法(diverted total synthesis, DTS)思想,通过全合成中的某一个高级中间体为起始原料,经过简单的反应顺利的合成出所计划的10个具有新颖结构的新型喜树碱类化合物(190系列及209系列)。其体外活性分别比喜树碱和SN-38高出10-30倍,内酯环稳定性也大大增强,对TOPI的抑制活性也比喜树碱高出10倍以上。
Tumor is a highly prevalent disease worldwide. Malignant neoplasm (cancer) has been the second largest threat to public health behind cardiovascular disease in developed countries, and the leading cause of death in rural areas of China. Therefore, there still remains an urgent need to develop new anticancer agents.
     Camptothecins (CPTs) are one of the most remarkable clinical anticancer drugs, which interact specifically with topoisomerase I. Among them, topotecan, irinotecan and belotecan have been launched and several other camptothecin analogues are currently at different stages of clinical development. Obviously, CPTs are hot areas of research.
     In the past decade, a lot of synthetic approaches of CPTs have been developed, some of them have been applied to the industrial production. However, these methods have some disadvantages, such as high cost, low stereoselectivity and so on. Althought lots of CPT analogues are in various stages of clinical trials, the instability of the E-ring of CPT has not been radically resolved.
     A new total synthesis route of CPT has been developed by our group, employing2-methoxy nicotinic acid as starting material,(R)-1-(2,2-dimethyl-[1,3]dioxolan-4-yl)propan-l-one as asymmetric induction reagent, in23%yield for in11steps (ee value100%). This11-step synthesis is a practical procedure for the large-scale preparation of CPT and its analogues. At present, this route is applied to the industrial production of SN-38at Qilu pharmaceutical.
     Moreover, utilizing the notion of "diverted total synthesis"(DTS) here, ten new camptothecin analogues have been synthesized. Series190and209exhibited10to30times superior antitumor activities in vitro to CPT and SN-38, more stability of E ring and over10times enzyme activity of inhibition of Top I than CPT.
引文
1:Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail, A. T.; Sim, G A. J. Am. Chem. Soc.1966,88,3888.
    2:Schultz A. G.; Rev.,1973,73,385.
    3:Cai, J. C., Hutchinson, C. R.; The alkaloids; New York:Academic,1983.101.
    4:Hsiang, Y. H., Hertzberg, R.; Hecht, S.; Liu, L. F.; J. Biol. Chem.,1985,260, 14873.
    5:Zunino, F.; Pratesi, G.; Expert Opin. Investig. Drugs,2004,13,269.
    6:Redinbo, M. R.; Stewart, L.; Kuhn, P.; Champouxetal, J. J., Science,1998,279, 1504.
    7:Tsao, Y. P.; Russo, A.; GNyamuswae tal, CancerRes.,1993,53,5908.
    8:Hertzberg, R. P.; Caranfa, M. J.; Hecht, S. M.; Biochemistry,1989,28,4629.
    9:Wani, M. C.; Nicholas, A. W.; Wall, M. E.; J. Med. Chem.,1986,29,2358.
    10:M. Huang, H. Y. Gao, Y. Chen, H. Zhu, Y. J. Cai, X. W. Zhang, Z. H. Miao, H. L. Jiang, J. Zhang, H. W. Shen, L. P. Lin, W. Lu, J. Ding, Clinical Cancer Research, 2007,13,1298.
    11:Wani, M. C.; Nicholas, A. W.; Manikumar, G.; Wall, M. E.; J. Med. Chem.,1987, 30,1774.
    12:Gao, H. Y.; Zhang, X. W.; Chen, Y.; Shen, H. W.; Pang,T.; Sun, J.; Xu, C. H.; Ding, J.; Li, C.; Lu, W. Bioorg. Med. Chem. Lett.2005,15,3233.
    13:A. J. Lu, Y. Y. Li, Q. D. You, S. Wang, Y. H. Liu, L. Ding, CN101475574A,8 July 2009.
    14:Wall, M. E.; Wani, M. C.; Nicholas, A. W.; Manikumar, G.; Tele, C.; Moore, L.; Truesdale, A.; Leitner, P.; Besterman, J. M.; J. Med. Chem.,1993,36,2689.
    15:Jew, S.; Kim, H. J.; Kim, M. G.; Kim, M. G.; Roh, E. Y.; Cho, Y.; Kim, J. K.; Cha, K. H.; Lee, K. K.; Han, H. J.; Choi, J. Y.; Lee, H.; Bioorg. Med. Chem. Lett.,1996, 6,845.
    16:Jew, S.; Kim, H. J.; Kim, M. G.; Roh, E. Y.; Hong, C. I.; Kim, J. K.; Lee, J. H.; Lee, H.; Park, H.; Bioorg. Med.Chem. Lett.,1999,9,3203.
    17:Xie, Z. F.; Ootsu, K.; Akimoto, H., Bioorg. Med. Chem. Lett.,1995,5,2189.
    18: Dallavalle, S.; Delsoldato, T.; Ferrari, A.; Merlini, L.; Penco, S.; Carenini, N.; Perego, P.; DeCesare, M.; Pratesi, G; Zunino, F.; J. Med. Chem., 2000, 43, 3963.
    19: Mitsui, I.; Kumazawa, E.; Hirota, Y.; Aonuma, M.; Sugimori, M.; Ohsuki, S.; Uoto, K.; Ejima, A.;Terasawa, H.; Sato, K.; Jpn. J. Cancer Res., 1995, 86, 776.
    20: Josien, H.; Bom, D.; Curran, D. P., Bioorg. Med. Chem. Lett., 1997, 7, 3189.
    21: Bom, D.; Curran, D. P.; Kruszewski, S.; Zimmer, S. G; Thompson, Strode. J.; Kohlhagen, G; Du, W.; Chavan, A. J.; Fraley, K. A.; Bingcang, A. L.; Latus, L. J.; Pommier, Y.; Burke, T. G; J. Med. Chem.,2000, 43, 3970.
    22: Luzzio, M. J.; Besterman, J. M.; Emerson, D. L.; Evans, M. G; Lackey, K.; Leitner, P. L.; Mclntyre, G; Morton, B.; Myers, P. L.; Peel, M.; et al. J. Med. Chem., 1995, 38, 395.
    23: Sawada, S.; Nokata, K.; Furuta, T.; Yokokura, T.; Miyasaka, T.; Chem. Pharm. Bull, 1991, 39,2574.
    24: Subrahmanyam, D.; Sarma, V. M.; Venkateswarlu, A.; Sastry, T. V.; Kulakarni, A. P.; Rao, D. S.; Reddy, K. V.; Bioorg. Med. Chem., 1999, 7, 2013.
    25: Subrahmanyam, D.; Venkateswarlu, A.; Venkateswara, Rao K.; Sastry, T. V.; Vandana, G; Kumar, S. A.; Bioorg. Med. Chem. Lett., 1999, 9, 1633.
    26.- Subrahmanyam, D.; Sarma, V. M.; Venkateswarlu, A.; Sastry, T. V.; Srinivas, A. S.; Krishna, C. V; Deevi, D. S.; Kumar, S. A.; Babu, M. J.; Damodaran, N. K. Bioorg. Med. Chem. Lett., 2000,10, 369.
    27: Wang, H. K.; Liu, S. Y; Hwang, K. M.; McPhail, A. T.; Lee, K. H.; Bioorg. Med. Chem. Lett., 1995,5,77.
    28: Chatterjee, A.; Digumarti, R.; Mamidi, R. N.; et al. ProcAm Soc. Clin. Oncol., 2002, 21 (abstract384).
    29: Cheng, K.; Rahier, N. J.; Eisenhauer, B. M.; Gao, R.; Thomas, S. J.; Hecht, S. M.; J. Am. Chem. Soc, 2005,127, 838.
    30: Hertzberg, R. P.; Caranfa, M. J.; Holden, K. G; Jakas, D. R.; Gallagher, G; Mattern, M. R.; Mong, S. M.; Bartus, J. O.; Johnson, R. K.; Kingsbury, W. D.; J. Med. Chem., 1989, 32,715.
    31: Nicholas, A. W.; Wani, M. C; Manikumar, G; Wall, M. E.; Kohn, K. W.; Pommier, Y; J. Med. Chem., 1990, 33, 972r
    32:Jew, S.; Kim, M. G; Kim, H.-J.; Roh, E. Y.; Cho, Y.; Kim, J. K.; Cha, K. H.; Lee, K. K.; Han, H. J.; Lee, H.; Bioorg. Med. Chem. Lett.,1996,6,849.
    33:Greenwald, R. B.; Pendri, A.; Conover, C.; Gilbert, C.; Yang, R.; Xia, J.;J. Med. Chem.,1996,39,1938.
    34:Greenwald, R. B.; Pendri, A.; Conover, C. D.; Lee, C.; Choe, Y. H.; Gilbert, C.; Martinez, A.; Xia, J.; Wu, D.; Hsue, M.; Bioorg. Med. Chem.,1998,6,551.
    35:Greenwald, R. B.; Zhao, H.; Xia, J.; Bioorg. Med. Chem.,2003,11,2635.
    36:Minko, T.; Paranjpe, P. V.; Qiu, B.; Lalloo, A.; Won, R.; Stein, S.; Sinko, P. J.; Cancer Chemother. Pharmacol.,2002,50,143.
    37:Lavergne, O.; Lesueur-Ginot, L.; Rodas, F. P.; Bigg D. C. H. Bioorg. Med. Chem. Lett.,1997,7,2235.
    38:Lavergne, O.; Lesueur-Ginot, L.; Pla, Rodas F.; Kasprzyk, P. G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A. M.; Harnett, J.; Pons, D.; Camara, J.; Bigg D. C.;J. Med. Chem.,1998,41,5410.
    39:Gelderblom, H.; Salazr, R.; Verweij, J.; Pentheroudakis, G.; de Jonge MJA, Devlin, M.; Hooije, C.; Seguy, F.; Obach, R.; Prunonosa, J.; Principe, P.; Twelves, C.; Clin. Cancer Res.2003,9,4101.
    40:Sawada, S.; Yokokura,t.;Ann. N.YAcad. Sci.,1996,803,13.
    41:Wang, H.K.; Morris-Natschke, S L.; Lee, K.H.; MedRes.Rev,1997,17,367.
    42:Wall, M .E.;.Wani, M.C.; Ann. N.YAcad. Sci.,1996,803,1.
    43:Saito, K.; Sudo, H.; Yamazakietal, M.; PlantCellRep.,2001,20,267.
    44:Sudo, H.; Yamakawa, T.; Yamazakietal, M.; BiotechnologyLett,,2002,24,359.
    45:Fulzele, D.P.; Satdive,R.K.; Pol, B.B.; PlantaMed.,2001,67,150.
    46:Sakato, K.; Tanaka, H.; Mukai, N.; Misawa, M. Agricultural and Biological Chemistry,1974,38,217.
    47:Saito, K.; Sudo, H.; Yamazaki, M.; Koseki-Nakamura, M.; Kitajima, M.; Takayama, H.; Aimi, N. Plant Cell Reports,2001,20,267.
    48:Brown, R. T.; Liu, J.; Santos, C. A. M. Tetrahedron Lett.,2000,41,859.
    49:Kitajima, M.; Yoshida, S.; Yamagata, K.; Nakamura, M.; Takayama, H.; Saito, K.; Seki, H.; Aimi, N. Tetrahedron 2002,58,9169.
    50:Kingsbury, W. D.; Boehm, J. C.; Jakas, D. R.; Holden, K. G.; Hecht, S. M.; Gallagher, G.; Caranfa, M. J.; McCabe, F. L.; Faucette, L. F.; Johnson, R. K.; Hertzberg, R. P. J. Med. Chem.1991,34,98.
    51:Sawada, S.; Okajima, S.; Aiyama, R.; Nokata, K.; Furuta, T.; Yokokura, T.; Sugino, E.; Yamaguchi, K.; Miyasaka, T. Chem. Pharm. Bull.1991,39,1446.
    52:Sawada, S.; Yokokura, T.; Miyasaka, T. Ann N.Y. Acad. Sci.1996,803,13,
    53:Ahn, S. K.; Choi, N. S.; Jeong, B. S.; Kim, K. K.; Journ, D. J.; Kim, J. K.; Lee, S. J.; Kim, J. W.; Hong, C.; Jew, S.-S. J. Heterocycl. Chem.2000,37,1141.
    54:Du, W.; Kaskar, B.; Blumbergs, P.; Subramanianm, P.-K.; Curran, D. P. Bioorg. Med. Chem.2003,11,451.
    55:Cao, Z.; Amstrong, K.; Shaw, M.; Petry, E.; Harris, N.; Synthesis 1998,1724.
    56:Dllavalle, S.; Ferrari, A.; Biasotti, B.; Merlini, L.; Penco, S.; Gallo, G.; Marzi, M.; Tinti, M. O.; Martinelli, R.; Pisano, C; Carminati, P.; Carenini, N.; Beretta, G.; Perego, P.; De Cesare, M.; Graziella, P.; Zunino, F. J. Med. Chem.2001,44,3264.
    57:Du, W. Tetrahedron 2003,59,8649.
    58:Curran, D. P.J. Chin. Chem. Soc. (Taipei) 1993,40,1.
    59:Curran, D. P.; Josien, H.; Bom, D.; Gabarda, A. E.; Du, W. Ann N. Y. Acad. Sci. 2000,922,112.
    60:Curran, D. P.; Liu, H.J. Am. Chem. Soc.1992,114,5863.
    61:Josien, H.; Curran, D. P. Tetrahedron 1997,53,8881.
    62:Wall, M. E.; Wani, M. C.; Natschke, S. M.; Nicholas, A. W. J. Med. Chem.1986, 29,1553.
    63:Ciufolini, M. A.; Roschangar, F. Angew. Chem. Int. Ed.1990,35,1692.
    64:Ciufolini, M. A.; Roschangar, F. Tetrahedron 1997,32,11049.
    65:Ciufolini, M. A.; Roschangar, F. Targets Hetrocycl. Syst.2000,4,25.
    66:Chavan, S. P.; Venkatraman, M. S. Tetrahedron Lett.1998,39,6745.
    67:Fortunak, J. M. D.; Mastrocola, A. R.; Mellinger, M.; Sisti, N. J.; Wood, J. L.; Zhuang, Z.-P. Tetrahedron Lett.1996,37,5679.
    68:Boger, D. L.; Hong, J. J. Am. Chem. Soc.1998,120,1218.
    69:Blagg, B. S. J.; Boger, D. L. Tetrahedron 2002,58,6343.
    70:Bennasar, M.-L.; Juan, C.; Bosch, J. Chem. Commun.2000,2459.
    71:Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.1992,114,10971.
    72:Comins, D. L.; Hong, H.; Gao, J. Tetrahedron Lett.1994,30,5331.
    73:Comins, D. L.; Hong, H.; Saha, J. K.; Gao, J. J. Org. Chem.1994,59,5120.
    74:Comins, D. L.; Nolan, J. M. Org. Lett.2001,3,4255.
    75:Corey E. J. J. Org. Chem.,1975,40,2140.
    76:Wani, M. C.; Nicholas, A. W.; Wall, M. E. J Med Chem,1987,30:2317-2319.
    77:Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.; Gu, R.-L. J. Org. Chem.,1997,62,6588.
    78:Fang, F. G.; Bankston, D. D.; Huie, E. M. et al. Tetrahedron,1997,53,10953.
    79:Blagg, B. S. J.; Boger, D. L. Tetrahedron,2002,58,6343.
    80:Curran, D. P.; Ko, S. B.; Josien, H. Angew. Chem. Int. Ed. Engl.,1995,34,2683.
    81:Zhou, H. B.; Liu, G. S.; Yao, Z. J. Org. Lett.,2007,9,2003.
    82:Liu, G.S.; Dong, Q. L.; Yao, Y. S.; Yao, Z. J. Org. Lett.,2008,10,5393.
    83:Zhang, L. P.; Bao, Y.; Kuang, Y. Y.; Chen, F. E. Helv. Chim. Acta.,2008,91,2057.
    84:Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.,1992,114,10971.
    85:Comins, D. L.; Nolan, J. M. Org. Lett.,2001,3,4255.
    86:Tang, C. J.; Babjak, M.; Anderson, R. J.; Greene, A. E.; Kanazawa, A. Org. Biomol. Chem.,2006,4,3757.
    87:Kanazawa, A.; Muniz, M. N.; Baumlova, B.; Ljungdahl, N.; Greene, A. E. Synlett, 2008,2275.
    88:Ejima, A.; Terasawa, H.; Sugimori, M.; et al. Tetrahedron Lett,1989,30,2639.
    89:Jew, S.S.; Ok, K. D.; Kim, H.J. et al. Tetrahedron:Asymmetry,1995,6,1245.
    90:Bennasar, M.-L.; Zulaica, E.; Juan, C.; Alonso, Y.; Bosch, J. J. Org. Chem.,2002, 67,7465.
    91:Ciufolini, M. A.; Roschangar, F. Angew. Chem. Int. Ed,1990,35,1692.
    1:Senilh, V.; Blechert, S.; Colin, M.; et al. J. Nat. Prod.,1984,47,131.
    2:Njardarson, J. T.; Gaul, C.; Shan, D.; Huang, X.-Y.; Danishefsky, S. J.; J. Am. Chem. Soc.2004,126,1038.
    3:Priel, E.; Showalter, S. D.; Blair, D. G AIDS Res. Hum. Retroviruses,1991,7,65.
    4:Wall, M. E.; Wani, M. C.; Natschke, S. M.; Nicholas, A. W. J. Med. Chem.,1986, 29,1553.
    5:Lavergne, O.; Lesueur-Ginot, L.; Rodas, F. P.; Bigg D. C. H.; Bioorg. Med. Chem. Lett.,1997,7,2235.
    6:Lavergne, O.; Lesueur-Ginot, L.; PlaRodas, F.; Kasprzyk, P. G.; Pommier, J.; Demarquay, D.; Prevost, G.; Ulibarri, G.; Rolland, A.; Schiano-Liberatore, A. M.; Harnett, J.; Pons, D.; Camara, J.; Bigg, D. C.; J. Med. Chem.,1998,41,5410.
    7:Olivier Lavergne, Daniele Demarquay, Philipg Kasprzyk, Dennis C. H. Bigg, Annals of the New York Academy of Sciences,100-111.
    8:Tagawa, H.; Terasawa, H.; Ejima, A.; Chem.Pharm.Bull.,1989,37,3382.
    9:Wall, M.E.; Wani.M.C.; J. Med. Chem.,1980,23,554.
    10:Tagawa, H.; Terasawa, H.; Ejima, A.; Tetrahedron Lett.,1989,30,263.
    11:Henegar, K. E.; Ashford, S. W.; Baughman, T. A.; Sih, J. C.; Gu, R.-L. J. Org. Chem.,1997,62,6588.
    12:Jain, R.; Roschangar, F.; Ciufolini, M. A.; Tetrahedron Lett.1995,36,3307.
    13:Ciulfolini, M.A.; Roschanger, F., Angew. Chem. In t. Engl,1996,35,1692.
    14:Jew, S. S.; Roh, E. Y.; Kim, H. J.; Kim, M. G.; Park, H. G. Tetrahedron: Asymmetry 2000,11,3985.
    15:Kuang, Y. Y.; Chen, F. E.; Org. Prep. Proced. Int.,2004,36,331.
    16:Haddad, M.; Larcheveque, M.; Syn. Comm.,2003,33,687.
    17:Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.1992,114,10971.
    18:Comins, D. L.; Hong, H.; Gao, J. Tetrahedron Lett.1994,30,5331.
    19:Comins, D. L.; Nolan, J. M. Org. Lett.2001,3,4255.
    20:Lazaar, J.; Rebstock, A.-S.; Mongin, F.; Godard, A.; Trecourt, F.; Marsais,F.; Queguiner, G.; Tetrahedron 2002,58,6723.
    21:Lazaar, J.; Hoarau, C.; Mongin, F.; Trecourt, F.; Godard, A.; Queguiner, G; Marsais, F.; Tetrahedron Lett.2005,46,3811.
    22:Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.1992,114,10971.
    23:Tamotsu, F.; Yutaka, U.; Makoto, F.; et al, Bull. Chem. Soc. Jpn.1990,63,1894.
    24:Hui, C. W.; Lee, H. K.; Henry N. C. Wong; Tetrahedron Lett.2002,43,123.
    25:Mikoshiba, H.; Mikami, K.; Nakai, T., Heterocycles,2001,54,585.
    26:Bowman, W. R; Elsegood, M. R. J.; Stein, T.; Weaver, G W.; Organic and Biomolecular Chemistry,2007, 5,103.
    27:Mekouar, K.; Genisson, Y.; Leue, S.; Greene, A. E.; J. Org. Chem.2000,65,5212.
    28:Fang, F. G.; Bankston, D. D.; Huie, E. M.; et al, Tetrahedron 1997,53,10953.
    29:Grillet, F.; Baumlova, B.; Prevost, G.; et al, Bioorg. Med Chem. Lett.,2008,18, 2143.
    30:Comins, D. L.; Baevsky, M. F.; Hong, H. J. Am. Chem. Soc.1992,114,10971.
    31:Moreno-Dorado, F. J.; Guerra. F. M.; Ortega, M. J.; et al, Tetrahedron: Asymmetry.2003,14,503.

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