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

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Wall ME, Wani MC, Nicholas AW, Manikumar G, Tele C, Moore L, Truesdale A, Leitner P, Besterman JM

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

J Med Chem. 1993 Sep 3;36(18):2689-700.

PubMed ID
8410981 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
CamptothecinDNA topoisomerase 1IC 50 (nM)680N/AN/ADetails
TopotecanDNA topoisomerase 1IC 50 (nM)1000N/AN/ADetails