苯并[b]吖啶系列中迈克尔受体和烯醇酯的设计、合成及细胞毒性活性

Design, synthesis, and cytotoxic activity of Michael acceptors and enol esters in the benzo[b]acronycine series.

作者信息

Doan Thi Mai Huong, Gaslonde Thomas, Michel Sylvie, Koch Michel, Tillequin François, Bailly Christian, David-Cordonnier Marie-Hélène, Pfeiffer Bruno, Léonce Stéphane, Pierré Alain

机构信息

Laboratoire de Pharmacognosie de l'Université René Descartes, U.M.R./C.N.R.S. n8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, F-75006 Paris, France.

出版信息

Chem Pharm Bull (Tokyo). 2005 Aug;53(8):919-22. doi: 10.1248/cpb.53.919.

DOI:10.1248/cpb.53.919

PMID:16079520

Abstract

A series of 2-acyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (4-6) was prepared by treatment of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (3) with an excess of an appropriate acyl chloride in the presence of aluminum chloride. Treatment of (+/-)-cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (9, 10) or (+/-)-cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (2, 11) with hydrochloric acid gave the corresponding 2-acyloxy-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones, exemplified by acetate 7 and butyrate 8. None of the Michael acceptors 4-6 showed significant antiproliferative activity. Enol esters 7 and 8 were markedly cytotoxic toward L1210 leukemia cells, with IC50 values within the same range of magnitude as (+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (S23906-1), currently under phase I clinical trials. In contrast with S23906-1, enol esters 7 and 8 were not reactive toward purified DNA.

摘要

通过在氯化铝存在下，用过量的适当酰氯处理6-甲氧基-3,3,14-三甲基-3,14-二氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮（3），制备了一系列2-酰基-6-甲氧基-3,3,14-三甲基-3,14-二氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮（4 - 6）。用盐酸处理（±）-顺式-1-羟基-2-酰氧基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮（9, 10）或（±）-顺式-1,2-二酰氧基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮（2, 11），得到相应的2-酰氧基-6-甲氧基-3,3,14-三甲基-3,14-二氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮，以乙酸酯7和丁酸酯8为例。迈克尔受体4 - 6均未显示出显著的抗增殖活性。烯醇酯7和8对L1210白血病细胞具有明显的细胞毒性，其IC50值与目前处于I期临床试验的（±）-顺式-1,2-二乙酰氧基-6-甲氧基-3,3,14-三甲基-1,2,3,14-四氢-7H-苯并[b]吡喃并[3,2-h]吖啶-7-酮（S23906-1）处于同一数量级范围内。与S23906-1相反，烯醇酯7和8对纯化的DNA无反应性。