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ID: ALA1131261

Journal: J Med Chem

Title: Synthesis and antitumor activity of ring A- and F-modified hexacyclic camptothecin analogues.

Authors: Sugimori M, Ejima A, Ohsuki S, Uoto K, Mitsui I, Kawato Y, Hirota Y, Sato K, Terasawa H.

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

CiteXplore: 9632364

DOI: 10.1021/jm970765q