Structural optimization and biological screening of a steroidal scaffold possessing cucurbitacin-like functionalities as B-Raf inhibitors

Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting the commonly occurring mutated B-Raf in melanoma has become a practical method for the development of drugs and drug candidates. In order to expand upon the currently reported structural scaffolds used to target the MAPK pathway, molecular docking studies led to the installation an α,β-unsaturated ketone side chain, related to the cucurbitacin class of natural products, on to an estrone core via an aldol condensation reaction, along with installation of the Δ^9,11 olefin to assemble what has been defined as a pseudo-cis configuration at the B/C ring juncture. Combination of these cucurbitacin-like features resulted in a compound with an enhanced biological profile against the A-375 mutant B-Raf cell line, in regards to their cytotoxicity and inhibitory activity toward phosphorylated extracellular-signal-regulated kinase (ERK). A hybrid scaffold: Molecular docking studies resulted in the design of hybrid compounds containing the α,β-unsaturated ketone of cucurbitacin D, a triterpene natural product, and an estrone core, along with a Δ^9,11 olefin. When evaluated in A-375 mutant B-Raf cells, compounds with this combination of cucurbitacin-like and steroidal features exhibited potent inhibition of phosphorylated extracellular-signal-regulated kinase (ERK).