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

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-alpha-rhamnoside (79a), strophanthidol-L-alpha-rhamnoside (92), and digitoxigenin-L-alpha-rhamnoside (97) were identified as the most potent steroids demonstrating broad anticancer activity at 10-100 nM concentrations and selectivity (nontoxic at 3 mu M against NIH-3T3, MEF, and developing fish embryos). Further analyses indicate that these molecules show a general mode of anticancer activity involving DNA-damageupregulation that subsequently induces apoptosis.


Publié dans:
Journal Of The American Chemical Society, 141, 12, 4849-4860
Année
Mar 27 2019
Publisher:
Washington, AMER CHEMICAL SOC
ISSN:
0002-7863
Mots-clefs:
Laboratoires:




 Notice créée le 2019-06-18, modifiée le 2019-12-05


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