Abstract |
The effect of 7-alkyl substitutions on growth inhibition in seven Camptothecin ( CPT) ring systems with various groups at the ten position was evaluated in three 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 persistence of cleavage complexes on antiproliferative activity, a post-exposure recovery period in drug-free medium was incorporated into the growth inhibition assay. This modification produced on average a twofold reduction in the growth inhibition endpoint (the IC50), suggesting a greater apoptotic response. The results further revealed a three log range in potency from a mean IC50 of 2 nM (7-butyl-10,11-methylenedioxy-CPT) to 2.5 microM (7-bromomethyl-10-hydryoxy-CPT). Increasing 7-alkyl chain length in six of the ten-substituted CPTs enhanced potency, which was directly correlated with persistence of topoisomerase I-induced DNA cleavage complexes in 10-hydroxy, 10-methoxy, and 10,11-methylenedioxy substituted CPTs. Modeling of the binding mode of 7-butyl-10-amino-CPT revealed a direct hydrogen bond contact for the 10-amino to the side chain of Glu-356 of Core Subdomain I of top1 in addition to known contacts found for other camptothecins. More important, residues 350-356 and 425-431 of Core Subdomain I may provide induced fit stabilization to the lipophilic alkyl moiety at the seven position.
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Authors | David J Adams, Mateus Webba da Silva, James L Flowers, Glenda Kohlhagen, Yves Pommier, O Michael Colvin, Govindarajan Manikumar, Mansukh C Wani |
Journal | Cancer chemotherapy and pharmacology
(Cancer Chemother Pharmacol)
Vol. 57
Issue 2
Pg. 135-44
(Jan 2006)
ISSN: 0344-5704 [Print] Germany |
PMID | 16151810
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Antineoplastic Agents, Phytogenic
- Camptothecin
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Topics |
- Antineoplastic Agents, Phytogenic
(chemistry, pharmacology)
- Apoptosis
(drug effects)
- Breast Neoplasms
(pathology)
- Camptothecin
(analogs & derivatives, chemistry, pharmacology)
- Cell Proliferation
(drug effects)
- Dose-Response Relationship, Drug
- Female
- Humans
- Tumor Cells, Cultured
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