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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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|
Faculty of Life and Health Sciences > School of Pharmacy and Pharmaceutical Science
|Research Institutes and Groups:||Biomedical Sciences Research Institute|
Biomedical Sciences Research Institute > Molecular Medicine
Biomedical Sciences Research Institute > Molecular Medicine > Transcriptional Regulation & Epigenetics
|Deposited By:||Dr Mateus Webba da Silva|
|Deposited On:||03 May 2011 10:56|
|Last Modified:||04 Dec 2012 14:25|
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