Conformationally restricted analogues of psorospermin: Design, synthesis, and bioactivity of natural-product-related bisfuranoxanthones

Robert A. Heald, Thomas S. Dexheimer, Hariprasad Vankayalapati, Adam Siddiqui-Jain, Lajos Z. Szabo, Mary C. Gleason-Guzman, Laurence Hurley

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The antileukemic xanthone psorospermin is a topoisomerase II-dependent DNA alkylator in advanced preclinical development. Efforts have been made to further understand the structural requirements of its mechanism of action through the synthesis of ring-constrained analogues, based on the skeleton of the bisfuranoxanthone natural products. Molecules were designed that contain the bisfuran and xanthone portions of naturally occurring psorofebrins, and molecular modeling was used to assess their DNA alkylating potential and to refine the structures. A short, diastereoselective synthetic process to access bisfuranoxanthones was developed, culminating in the first total synthesis of (±)-isohydroxypsorofebrin. Two compounds designed and synthesized were of particular interest, chlorohydrin 7 and epoxide 6, which are reactive analogues of the natural product isohydroxypsorofebrin. The chlorohydrin retains the psorospermin-like DNA alkylation characteristics despite its rigid structure and high innate affinity for DNA. Molecular modeling has been used to rationalize the increased activity of the chlorohydrin. The chlorohydrin and epoxide show increased cytotoxicity compared to isohydroxypsorofebrin against a range of human tumor cell lines.

Original languageEnglish (US)
Pages (from-to)2993-3004
Number of pages12
JournalJournal of Medicinal Chemistry
Volume48
Issue number8
DOIs
StatePublished - Apr 21 2005

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Chlorohydrins
Bioactivity
Biological Products
Molecular modeling
DNA
Epoxy Compounds
Rigid structures
Type II DNA Topoisomerase
Alkylating Agents
Alkylation
Cytotoxicity
Tumor Cell Line
Skeleton
Tumors
Cells
Molecules
psorospermin

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Conformationally restricted analogues of psorospermin : Design, synthesis, and bioactivity of natural-product-related bisfuranoxanthones. / Heald, Robert A.; Dexheimer, Thomas S.; Vankayalapati, Hariprasad; Siddiqui-Jain, Adam; Szabo, Lajos Z.; Gleason-Guzman, Mary C.; Hurley, Laurence.

In: Journal of Medicinal Chemistry, Vol. 48, No. 8, 21.04.2005, p. 2993-3004.

Research output: Contribution to journalArticle

Heald, Robert A. ; Dexheimer, Thomas S. ; Vankayalapati, Hariprasad ; Siddiqui-Jain, Adam ; Szabo, Lajos Z. ; Gleason-Guzman, Mary C. ; Hurley, Laurence. / Conformationally restricted analogues of psorospermin : Design, synthesis, and bioactivity of natural-product-related bisfuranoxanthones. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 8. pp. 2993-3004.
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