Novel 7-substituted camptothecins with potent antitumor activity

S. Dallavalle, T. Delsoldato, A. Ferrari, L. Merlini, S. Penco, N. Carenini, P. Perego, M. De Cesare, G. Pratesi, F. Zunino

Research output: Contribution to journalArticlepeer-review

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 IC50 values in the 0.05-1 μM 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.

Original languageEnglish
Pages (from-to)3963-3969
Number of pages7
JournalJournal of Medicinal Chemistry
Volume43
Issue number21
DOIs
Publication statusPublished - Oct 19 2000

ASJC Scopus subject areas

  • Organic Chemistry

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