The α-hydroxy-β-dicarbonyl moiety is a common structural motif in variety of natural products and pharmaceuticals, such as kjellmanianone, hamigeran A, or doxycycline. Moreover, this functional unit appears in key metabolites of pharmaceutically important natural products obtained from <b><i>Hamigera tarangaensis. </i></b>Motivated from these observations we have synthesized a library of 20 compounds. These compounds were prepared from 2,3-diketoesters by a highly enantioselective carbonyl-ene transformation using chiral copper (II) catalysts. To evaluate their potential for anticancer activity, we tested these compounds for cell growth inhibition on nine different cancer panels, representing diverse histologies i.e., leukemia, melanoma, and cancers of lung, colon, kidney, ovary, breast, prostate, and central nervous system. This screening identified a lead compound NSC781411 which selectively inhibits the growth of breast cancer cells. To elucidate the underlying molecular mechanisms, we examined the effect of this compound on the clonogenic potential using well-established representatives of estrogen-responsive (MCF7) and estrogen-refractory (MDA-MB-231) human breast cancers. These experiments showed that the compound inhibits clonogenicity and alters expression of proteins involved in growth and apoptosis. mRNA analysis of the NCI60 data suggested significant positive correlation of NSC781411 to response to radiation, opening the possibility of an effective complimentary treatment to the commonly used patient therapy (radiation).

Cytotoxicity study of α-hydroxy-β-dicarbonyl bearing synthetic metabolites of poecilosclerid sponge

253rd National Meeting (2017)

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