Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations.
Plant antitumor agents. 25. Total synthesis and antileukemic activity of ring A substituted camptothecin analogues. Structure-activity correlations.
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DOI：
10.1021/jm00393a016
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发表时间：
1987-10
影响因子：
7.3
通讯作者：
M. Wani;A. W. Nicholas;G. Manikumar;Monroe E. Wall
中科院分区：
文献类型：
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作者：
M. Wani;A. W. Nicholas;G. Manikumar;Monroe E. Wall
通过全合成制备了抗肿瘤剂20(S)-喜树碱的19个外消旋环A取代的类似物，并评估了针对KB细胞培养物的体外细胞毒活性和针对L1210的体内抗白血病活性。这些化合物在 C11 处具有多种取代基，旨在赋予环系统多种电子、空间和亲脂效应的组合。作为同时研究的一部分而制备的一些 C10 取代衍生物以及 C10,C11 双取代类似物也已包括在内以进行一般比较。除了氰基衍生物之外，11 位取代的化合物仅表现出适度的体外和体内活性，并且对取代基的性质显着不敏感。相比之下，9-和10-取代的化合物在体外和体内均表现出相当高水平的剂量效力和活性。
Nineteen racemic ring A substituted analogues of the antitumor agent 20(S)-camptothecin were prepared by total synthesis and evaluated for in vitro cytotoxic activity against KB cell culture and in vivo antileukemic activity against L1210. These compounds bore a wide variety of substituents at C11 designed to confer upon the ring system a broad range of combinations of electronic, steric, and lipophilic effects. A few C10-substituted derivatives as well as C10,C11-disubstituted analogues prepared as part of a concurrent study have also been included for general comparison. With the notable exception of the cyano derivative, the 11-substituted compounds displayed only modest in vitro and in vivo activities, and there was a remarkable insensitivity toward the nature of the substituent. In contrast, the 9- and 10-substituted compounds exhibited a considerably higher level of dose potency and activity both in vitro and in vivo.