Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

作     者：Martinez, EJ Owa, T Schreiber, SL Corey, EJ 

作者机构：Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA Harvard Univ Howard Hughes Med Inst Cambridge MA 02138 USA 

出 版 物：《PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA》 (美国国家科学院汇刊)

年 卷 期：1999年第96卷第7期

页      面：3496-3501页

核心收录：

学科分类：07[理学] 08[工学] 

主　　题：抗肿瘤药 烷基化/化学 抗肿瘤药 烷基化/毒性 博来霉素/毒性 喜树碱/毒性 细胞分裂/药物作用 顺铂/毒性 交联试剂/化学 交联试剂/毒性 DNA拓扑异构酶类 Ⅰ型/代谢 DNA 肿瘤/代谢 二恶茂类/化学 二恶茂类/毒性 多柔比星/毒性 依托泊甙/毒性 异喹啉类/化学 异喹啉类/毒性 丝裂霉素/毒性 模型 分子 分子结构 肿瘤蛋白质类/代谢 紫杉酚/毒性 苯邻二甲酰亚胺类/化学 苯邻二甲酰亚胺类/毒性 构效关系 四氢异喹啉类 肿瘤细胞 培养的 女(雌)性 人类 男(雄)性 

摘      要：A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC50 = 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents, Phthalascidin and Et 743 show undiminished potency in camptothecin- and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials, The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.