Plant sterols as selective DNA polymerase beta lyase inhibitors and potentiators of bleomycin cytotoxicity

Bioorganic & Medicinal Chemistry
Shi-Sheng LiS M Hecht

Abstract

In a survey of crude plant extracts for DNA polymerase beta lyase inhibitors, the hexanes extracts of Cladogynus orientalis, Hymenache donacifolia, and Heteropsis integerrima, and the methyl ethyl ketone extract of Acacia pilispina were found to exhibit good inhibition of the dRP lyase activity of DNA polymerase beta. Bioassay-guided fractionation of these extracts led to the isolation of three DNA polymerase beta lyase inhibitory phytosterols, namely stigmasterol (1) and beta-sitosterol (2), isolated from the hexanes extracts, and beta-sitosterol-beta-d-glucoside (3), isolated from the methyl ethyl ketone extract. Compounds 1-3 inhibited the DNA polymerase beta lyase activity with IC(50) values of 43.6, 43.3, and 72.4 microM, respectively. Compounds 1 and 2 were found capable of potentiating the action of bleomycin in cultured human tumor cells, consistent with the possibility that lyase inhibitors may find utility in vivo.

Citations

Feb 3, 2005·Nature Reviews. Cancer·Jingyang Chen, JoAnne Stubbe
Jul 17, 2012·Antioxidants & Redox Signaling·Jason L ParsonsRicky A Sharma
Sep 3, 2016·Genes·Elisa MentegariEmmanuele Crespan
Jan 10, 2017·Chemical Research in Toxicology·A S Prakasha GowdaThomas E Spratt
Aug 11, 2020·Bioorganic & Medicinal Chemistry·Sasha M DaskalovaSidney M Hecht
Mar 18, 2008·Bioorganic & Medicinal Chemistry·Zhijie GaoSidney M Hecht

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