期刊
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 141, 期 12, 页码 4849-4860出版社
AMER CHEMICAL SOC
DOI: 10.1021/jacs.8b12870
关键词
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资金
- NIH [1R01GM111476, 1DP2GM114850]
- NSF [CHE-0840456]
- NSF CAREER [CHE-1351400]
- Office of Naval Research (ONR) [N00014-17-1-2529]
- Cornell Imaging Center [NIH 1S10RR025502]
- zebrafish husbandry and microinjection/imaging facility [NIH R01 NS026593]
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.
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