Novel 7-substituted camptothecins with potent antitumor activity.
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| Abstract |
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.
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| Authors | S Dallavalle, T Delsoldato, A Ferrari, L Merlini, S Penco, N Carenini, P Perego, M De Cesare, G Pratesi, F Zunino |
| Journal | Journal of medicinal chemistry (J Med Chem) Vol. 43 Issue 21 Pg. 3963-9 (Oct 19 2000) ISSN: 0022-2623 [Print] United States |
| PMID | 11052801 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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