Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity

Ingrid M. Fellows, Michael Schwaebe, Thomas S. Dexheimer, Hariprasad Vankayalapati, Mary Gleason-Guzman, Jeffrey P. Whitten, Laurence Hurley

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Psorospermin is a natural product that has been shown to have activity against drug-resistant leukemia lines and AIDS-related lymphoma. It has also been shown to alkylate DNA through an epoxide-mediated electrophilic attack, and this alkylation is greatly enhanced at specific sites by topoisomerase II. In this article, we describe the synthesis of the two diastereomers of O5-methyl psorospermin and their in vitro activity against a range of solid and hematopoietic tumors. The diastereomeric pair (±)-(2′ R,3′ R) having the naturally occurring enantiomer (2′ R,3′ R) is the most active across all the cell lines and shows approximately equal activity in both drug-sensitive and drug-resistant cell lines. In subsequent studies using all four enantiomers of O5-methyl psorospermin, the order of biological potency is (2′ R,3′ R) > (2′ R,3′ S) = (2′ S,3′ R) > (2′ S,3′ S). This order of potency is also found in the topoisomerase II-induced alkylation of O5-methyl psorospermin and can be rationalized by molecular modeling of the psorospermin-duplex binding complex. Therefore, this study defines the optimum stereochemical requirements for both the topoisomerase II-induced alkylation of DNA and the biological activity by psorospermin and its O5-methyl derivatives. Finally, (2′ R,3′ R) psorospermin was found to be as effective as gemcitabine in slowing tumor growth in vivo in a MiaPaCa pancreatic cancer model. In addition, (2′ R,3′ R) psorospermin in combination with gemcitabine was found to show an at least additive effect in slowing tumor growth of MiaPaCa.

Original languageEnglish (US)
Pages (from-to)1729-1739
Number of pages11
JournalMolecular Cancer Therapeutics
Volume4
Issue number11
DOIs
StatePublished - Nov 2005

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Type II DNA Topoisomerase
Alkylation
DNA
gemcitabine
AIDS-Related Lymphoma
Pharmaceutical Preparations
Cell Line
Neoplasms
In Vitro Techniques
psorospermin
Epoxy Compounds
Growth
Biological Products
Pancreatic Neoplasms
Leukemia

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity. / Fellows, Ingrid M.; Schwaebe, Michael; Dexheimer, Thomas S.; Vankayalapati, Hariprasad; Gleason-Guzman, Mary; Whitten, Jeffrey P.; Hurley, Laurence.

In: Molecular Cancer Therapeutics, Vol. 4, No. 11, 11.2005, p. 1729-1739.

Research output: Contribution to journalArticle

Fellows, Ingrid M. ; Schwaebe, Michael ; Dexheimer, Thomas S. ; Vankayalapati, Hariprasad ; Gleason-Guzman, Mary ; Whitten, Jeffrey P. ; Hurley, Laurence. / Determination of the importance of the stereochemistry of psorospermin in topoisomerase II-induced alkylation of DNA and in vitro and in vivo biological activity. In: Molecular Cancer Therapeutics. 2005 ; Vol. 4, No. 11. pp. 1729-1739.
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AU - Dexheimer, Thomas S.

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AU - Hurley, Laurence

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