PLANT ANTITUMOR AGENTS .30. SYNTHESIS AND STRUCTURE-ACTIVITY OF NOVELCAMPTOTHECIN ANALOGS

A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituent s. Topoisomerase I (T-I) inhibition data (IC50) have been obtained by standard procedures. In general, substitution at the 9 or 10 positions with amino, halogeno, or hydroxyl groups in compounds with 20S config uration results in compounds with enhanced T-1 inhibition. Compounds i n the 20RS configuration were less active in vitro and in vivo and tho se in the 20R configuration were inactive. (Compounds with 10,11-methy lenedioxy substitution on ring A displayed a marked increase in potenc y in the T-I inhibition assay. The activities of some of the analogs a s determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-1 inhibition. A num ber of water-soluble analogs such as 20-glycinate esters, 9-glycinamid es, or hydrolyzed lactone salts were prepared and tested in in vitro a nd in vivo assays. In general, these compounds were less active than C PT both in terms of T-I inhibition and life prolongation in the L-1210 assay. However, certain 20-glycinate esters showed good in vivo activ ity after iv administration.