Novel 7-substituted camptothecins with potent antitumor activity

The natural alkaloid camptothecin is the lead compound of a new class of an titumor agents with a unique mechanism of action (i.e. inhibition of DNA to poisomerase I). The pharmacological interest of these agents has generated a large number of derivatives and analogues endowed with potent cytotoxic a ctivity, two of them being in clinical use as antitumor drugs. We have synt hesized a new series of camptothecins substituted in position 7 with an alk yl 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 cytotoxici ty against a topotecan-resistant H460 cell subline (H460/TPT) and a cisplat in-resistant ovarian carcinoma subline (IGROV-1/Pt 1). In an in vivo evalua tion of the antitumor activity, 5a appeared significantly more effective th an topotecan in the H460 tumor model and comparable with topotecan in a sma ll-cell lung carcinoma model and a colon carcinoma model. The efficacy and good tolerability of this compound increase interest for further preclinica l development.