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Cancer Chemotherapy and Pharmacology

, Volume 57, Issue 2, pp 135–144 | Cite as

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

  • David J. AdamsEmail author
  • Mateus Webba da Silva
  • James L. Flowers
  • Glenda Kohlhagen
  • Yves Pommier
  • O. Michael. Colvin
  • Govindarajan Manikumar
  • Mansukh C. Wani
Original Article

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.

Keywords

Camptothecin Topoisomerase I Religation assay Breast cancer 

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

Notes

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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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • David J. Adams
    • 1
    Email author
  • Mateus Webba da Silva
    • 1
  • James L. Flowers
    • 1
  • Glenda Kohlhagen
    • 3
  • Yves Pommier
    • 3
  • O. Michael. Colvin
    • 1
  • Govindarajan Manikumar
    • 2
  • Mansukh C. Wani
    • 2
  1. 1.Department of Medicine, Duke Comprehensive Cancer CenterDuke University Medical CenterDurhamUSA
  2. 2.Research Triangle Institute InternationalResearch Triangle ParkUSA
  3. 3.Laboratory of Molecular Pharmacology, NIHNational Cancer InstituteBethesdaUSA

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