Modular Total Synthesis and Cell-Based Anticancer Activity Evaluation of Ouabagenin and Other Cardiotonic Steroids with Varying Degrees of Oxygenation

Journal of the American Chemical Society
Hem Raj KhatriPavel Nagorny

Abstract

A Cu(II)-catalyzed diastereoselective Michael/aldol cascade approach is used to accomplish concise total syntheses of cardiotonic steroids with varying degrees of oxygenation including cardenolides ouabagenin, sarmentologenin, 19-hydroxysarmentogenin, and 5- epi-panogenin. These syntheses enabled the subsequent structure activity relationship (SAR) studies on 37 synthetic and natural steroids to elucidate the effect of oxygenation, stereochemistry, C3-glycosylation, and C17-heterocyclic ring. Based on this parallel evaluation of synthetic and natural steroids and their derivatives, glycosylated steroids cannogenol-l-α-rhamnoside (79a), strophanthidol-l-α-rhamnoside (92), and digitoxigenin-l-α-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 μM against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damage upregulation that subsequently induces apoptosis.

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Citations

Jan 17, 2020·Chemistry : a European Journal·Daniel TownsendAlexander J A Cobb
Jul 7, 2020·Molecular Diversity·Salvador Enrique Meneses-SagreroRamón Enrique Robles-Zepeda
Feb 5, 2021·The Journal of Organic Chemistry·Shogo WatanabeAtsuo Nakazaki
Oct 31, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yu-Pu Juang, Pi-Hui Liang
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Feb 27, 2021·European Journal of Medicinal Chemistry·Meng-Xue WeiJin-Hui Yang
Mar 30, 2021·Bioorganic & Medicinal Chemistry Letters·Patricia MoweryErin T Pelkey
May 6, 2021·Organic & Biomolecular Chemistry·Zhuo Wang, Chunngai Hui
Apr 4, 2021·ChemMedChem·Marcus J C Long, Yimon Aye
Jul 14, 2021·The Journal of Organic Chemistry·Zachary FejedelemPavel Nagorny
Aug 14, 2020·ACS Combinatorial Science·Jude I Ayogu, Amaechi S Odoh
Oct 27, 2020·Organic Letters·Shinsuke ShimizuMasayuki Inoue
Feb 26, 2020·Journal of Natural Products·Yulin RenA Douglas Kinghorn
Jul 14, 2020·Journal of the American Chemical Society·Min-Jing ChengChuang-Chuang Li

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