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-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.