Dallavalle S, Delsoldato T, Ferrari A, Merlini L, Penco S, Carenini N, Perego P, De Cesare M, Pratesi G, Zunino F
Dipartimento di Scienze Molecolari Agroalimentari, Sezione di Chimica, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
J Med Chem. 2000 Oct 19;43(21):3963-9. doi: 10.1021/jm000944z.
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 IC(50) values in the 0.05-1 microM 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.
天然生物碱喜树碱是一类具有独特作用机制（即抑制DNA拓扑异构酶I）的新型抗肿瘤药物的先导化合物。这些药物的药理特性引发了大量具有强大细胞毒性活性的衍生物和类似物的产生，其中两种已作为抗肿瘤药物用于临床。我们合成了一系列新的喜树碱，其7位被带有氰基和/或乙氧羰基的烷基或烯基链取代。这些化合物在体外对人非小细胞肺癌H460细胞系显示出强大的细胞毒性活性，其中大多数的IC(50)值在0.05 - 1 microM范围内，比用作参考化合物的拓扑替康更具活性。特别是7 - 氰基 - 20S - 喜树碱（5a）对拓扑替康耐药的H460细胞亚系（H460/TPT）和顺铂耐药的卵巢癌亚系（IGROV - 1/Pt 1）表现出高体外细胞毒性。在抗肿瘤活性的体内评估中，5a在H460肿瘤模型中比拓扑替康明显更有效，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耐受性增加了其进一步临床前开发的吸引力。
