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Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex

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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 μM (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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Abbreviations

top1:

Topoisomerase I

CPT:

Camptothecin

MD or MDO:

10,11-Methylenedioxy

ED:

10,11-Ethylenedioxy

MeO:

Methoxy

DFMD:

Difluoromethylenedioxy

CMMDC:

7-Chloromethyl-10,11-methylenedioxy-camptothecin

SN-38:

7-Ethyl-10-hydroxy-camptothecin

BACPT:

7-Butyl-10-amino-camptothecin

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Acknowledgements

This work was supported by NIH grant UO1 CA68697-02 and is dedicated to the memory of Dr. Monroe E. Wall, who inspired this research team and many other investigators committed to creating useful anticancer drugs from natural products.

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Authors and Affiliations

  1. Department of Medicine, Duke Comprehensive Cancer Center, Duke University Medical Center, Durham, NC, 27710, USA

    David J. Adams, Mateus Webba da Silva, James L. Flowers & O. Michael. Colvin

  2. Research Triangle Institute International, Research Triangle Park, NC, 27709, USA

    Govindarajan Manikumar & Mansukh C. Wani

  3. Laboratory of Molecular Pharmacology, NIH, National Cancer Institute, Bethesda, MD, 20892-4255, USA

    Glenda Kohlhagen & Yves Pommier

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  1. David J. Adams
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  2. Mateus Webba da Silva
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Correspondence to David J. Adams.

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Adams, D.J., Silva, M.W.d., Flowers, J.L. et al. Camptothecin analogs with enhanced activity against human breast cancer cells. I. Correlation of potency with lipophilicity and persistence in the cleavage complex. Cancer Chemother Pharmacol 57, 135–144 (2006). https://doi.org/10.1007/s00280-005-0007-6

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  • DOI: https://doi.org/10.1007/s00280-005-0007-6

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