Plant Antitumor Agents. 30. Synthesis and Structure Activity of Novel Camptothecin Analogs

Article abstract of DOI:10.1021/jm00070a013

A large number of camptothecin (CPT) analogs have been prepared in the 20S, 20RS, and 20R configurations with a number of ring A substituents.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 configuration results in compounds with enhanced T-1 inhibition.Compounds in the 20RS configuration were less active in vitro and in vivo and those in the 20R configuration were inactive.Compounds with 10,11-methylenedioxy substitution on ring A displayed a marked increase in potency in the T-I inhibition assay.The activities of some of the analogs as determined in a variety of in vivo assays including the L-1210 mouse leukemia assay were, in general, in accord with T-I inhibition.A number of water-soluble analogs such as 20-glycinate esters, 9-glycinamides, or hydrolyzed lactone salts were prepared and tested in in vitro and in vivo assays.In general, these compounds were less active than CPT both in terms of T-I inhibition and life prolongation in the L-1210 assay.However, certain 20-glycinate esters showed good in vivo activity after iv administration.