Plant antitumor agents. 30. Synthesis and structure activity of novel camptothecin analogs

• Published in: Journal of medicinal chemistry 1993-09, Vol.36 (18), p.2689-2700
• Main Authors: Wall, Monroe E, Wani, Mansukh C, Nicholas, Allan W, Manikumar, Govindarajan, Tele, Chhagan, Moore, Linda, Truesdale, Anne, Leitner, Peter, Besterman, Jeffrey M
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Camptothecin - analogs & derivatives; Camptothecin - chemical synthesis; Camptothecin - therapeutic use; Female; Humans; Leukemia L1210 - drug therapy; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred DBA; Molecular Conformation; Molecular Structure; Plants, Medicinal - chemistry; Stereoisomerism; Structure-Activity Relationship; Topoisomerase I Inhibitors; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• 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-I 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.