Novel 7-substituted camptothecins with potent antitumor activity
Novel 7-substituted camptothecins with potent antitumor activity
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DOI：
10.1021/jm000944z
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发表时间：
2000-10-19
影响因子：
7.3
通讯作者：
Zunino, F
中科院分区：
文献类型：
--
作者：
Dallavalle, S;Delsoldato, T;Zunino, F
天然生物碱喜树碱是一类新型抗肿瘤药物的先导化合物，具有独特的作用机制（即抑制DNA拓扑异构酶I）。这些药物的药理研究已经产生了大量具有强细胞毒活性的衍生物和类似物，其中两种被用作临床抗肿瘤药物。我们合成了一系列新的喜树碱，在7号位置被烷基或烯基链取代，其中含有氰基和/或碳氧基。这些化合物在体外对人非小细胞肺癌H460细胞系显示出较强的细胞毒活性，大多数化合物的IC50值在0.05-1 muM范围内，比拓扑替康作为对照化合物的活性更强。特别是7-氰-20 -喜树碱（5a）对拓扑替康耐药的H460细胞亚群（H460/TPT）和顺铂耐药的卵巢癌亚群（IGROV-1/Pt 1）显示出高的体外细胞毒性。在体内抗肿瘤活性评估中，5a在H460肿瘤模型中明显优于拓扑替康，在小细胞肺癌模型和结肠癌模型中与拓扑替康相当。该化合物的疗效和良好的耐受性增加了进一步临床前开发的兴趣。
The natural alkaloid camptothecin is the lead compound of a new class of antitumor agents with a unique mechanism of action (i.e. inhibition of DNA topoisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic activity, two of them being in clinical use as antitumor drugs. We have synthesized a new series of camptothecins substituted in position 7 with an alkyl or alkenyl chain bearing cyano and/or carbethoxy groups. These compounds showed potent cytotoxic activity in vitro against the human non-small-cell lung carcinoma H460 cell line, most of them exhibiting IC50 values in the 0.05-1 muM range, more active than topotecan used as a reference compound. In particular 7-cyano-20S-camptothecin (5a) showed high in vitro cytotoxicity against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplatin-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evaluation of the antitumor activity, 5a appeared significantly more effective than topotecan in the H460 tumor model and comparable with topotecan in a small-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinical development.