SYNTHESIS AND ANTITUMOR-ACTIVITY OF RING-A-MODIFIED AND RING-F-MODIFIED HEXACYCLIC CAMPTOTHECIN ANALOGS

Nineteen ring A- and F-modified hexacyclic analogues of camptothecin w ere synthesized by Friedlander condensation of appropriately substitut ed bicyclic amino ketones with tricyclic ketone and were evaluated for cytotoxicity and topoisomerase I inhibitory activity. Seventeen of th e compounds showed cytotoxic effects comparable or superior to those o f 7-ethyl-10-hydroxycamptothecin (SN-38) against mouse leukemia P388 a nd human tumor cell lines HOC-21 and QG-56. Introduction of a compact and inductively electron-withdrawing substituent such as a hydroxy, me thoxy, chloro, or fluoro group into position 5 of ring A of the hexacy clic compound remarkably increased the antitumor activity. The potency of topoisomerase I inhibition of these compounds showed good correlat ion with their cytotoxicity. Among them, the 4-methyl-5-fluoro hexacyc lic compound was the most potent of all and was 10 times as active as SN-38 in in vitro antitumor activity.