Structure-Activity Relationship of Alkyl Camptothecin Esters
- 25 January 2006
- journal article
- Published by Wiley in Annals of the New York Academy of Sciences
- Vol. 922 (1), 122-135
- https://doi.org/10.1111/j.1749-6632.2000.tb07031.x
Abstract
The cytotoxicity of camptothecin (CPT) esters 1-6 was measured. Like parental camptothecin, esters 2 and 3, but not 1, 4, 5, and 6, inhibited proliferation of human leukemia cells in culture and induced programmed cell death as assessed by flow cytometry studies. Exhibition of similar levels of antiproliferative activities of CPT 2 and 3 required different incubation time periods in cell cultures, with CPT and 3 requiring the shortest and longest periods, respectively. Both 2 and 3 were inactive against cells resistant to the semisynthetic CPT derivative 9-nitrocamptothecin and unable to stabilize DNA-topoisomerase I (Topo I) "cleavable complexes" in a cell-free system, suggesting that Topo I activity was required but insufficient for the mechanism of action of 2 and 3. Mouse liver homogenate converted esters to parental CPT, but the conversion rates were different with different esters. Of four tested esters in this experiment, ester 2 had the fastest conversion rate. In vivo studies showed that ester 2 had an exceptional lack of toxicity in nude mice, even at enormous doses, and demonstrated extensive activity against human breast and colon tumors grown as xenografts in immunodeficient nude mice, whereas no antitumor activity was observed for the other esters. In conclusion, ester 2 is a prodrug of the antitumor compound CPT, and it can be administered at very high doses in mice with no appearance of toxicity. This study provides a basis for further evaluation of CPT ester 2 as an investigational anticancer agent.Keywords
This publication has 23 references indexed in Scilit:
- Synthesis and Antitumor Activity of Novel Water Soluble Derivatives of Camptothecin as Specific Inhibitors of Topoisomerase IJournal of Medicinal Chemistry, 1995
- The synthesis and evaluation of flexible analogues of the topoisomerase I inhibitor, camptothecinBioorganic & Medicinal Chemistry Letters, 1994
- Synthesis of 18-Noranhydrocamptothecin Analogs Which Retain Topoisomerase I Inhibitory FunctionThe Journal of Organic Chemistry, 1994
- Catalytic Enantioselective Synthesis of 20(S)-Camptothecin: A Practical Application of the Sharpless Asymmetric Dihydroxylation ReactionThe Journal of Organic Chemistry, 1994
- Asymmetric synthesis of camptothecin alkaloids: A nine-step synthesis of (S)-camptothecinTetrahedron Letters, 1994
- Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activityJournal of Medicinal Chemistry, 1991
- Biochemical basis for the interactions of type I and type II topoisomerases with DNAPharmacology & Therapeutics, 1989
- Analogs of camptothecinJournal of Medicinal Chemistry, 1975
- Synthesis and biological evaluation of de-AB-camptothecinThe Journal of Organic Chemistry, 1974
- Plant Antitumor Agents. I. The Isolation and Structure of Camptothecin, a Novel Alkaloidal Leukemia and Tumor Inhibitor from Camptotheca acuminata1,2Journal of the American Chemical Society, 1966