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Camptothecin analogs with enhanced activity against human breastcancer cells. I. Correlation of potency with lipophilicity and persistence inthe cleavage complex

Adams, DJ, Webba da Silva, Mateus, Kohlhagen, G, Pommier, Y, Colvin, OM, Manikumar, G and Wani, MC (2005) Camptothecin analogs with enhanced activity against human breastcancer cells. I. Correlation of potency with lipophilicity and persistence inthe cleavage complex. Cancer Chemother Pharmacol, 57 . [Journal article]

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DOI: 10.1007/s00280-005-0007-6

Abstract

The effect of 7-alkyl substitutions on growthinhibition in seven Camptothecin (CPT) ring systemswith various groups at the ten position was evaluated inthree human breast cancer cell lines that model (1)hormone-sensitive (MCF-7/wt), (2) hormone insensitive(MDA-MB-231), or (3) alkylator-resistant (MCF-7/4-hc) forms of disease. To assess the impact of persistenceof cleavage complexes on antiproliferative activity, apost-exposure recovery period in drug-free medium wasincorporated into the growth inhibition assay. Thismodification produced on average a twofold reductionin the growth inhibition endpoint (the IC50), suggestinga greater apoptotic response. The results further revealeda three log range in potency from a mean IC50 of2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 lM(7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkylchain length in six of the ten-substituted CPTs enhancedpotency, which was directly correlated with persistenceof topoisomerase I-induced DNA cleavage complexes in10-hydroxy, 10-methoxy, and 10,11-methylenedioxysubstituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bondcontact for the 10-amino to the side chain of Glu-356 ofCore Subdomain I of top1 in addition to known contactsfound for other camptothecins. More important,residues 350–356 and 425–431 of Core Subdomain I mayprovide induced fit stabilization to the lipophilic alkylmoiety at the seven position.

Item Type:Journal article
Faculties and Schools:Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
Faculty of Life and Health Sciences
Research Institutes and Groups:Biomedical Sciences Research Institute > Genomic Medicine > Transcriptional Regulation & Epigenetics
Biomedical Sciences Research Institute > Genomic Medicine
Biomedical Sciences Research Institute
ID Code:18298
Deposited By: Dr Mateus Webba da Silva
Deposited On:03 May 2011 09:56
Last Modified:09 Dec 2015 10:56

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