Cucurbitacins are highly oxygenated tetracyclic triterpene natural products. They are known for their broad spectrum of biological activities such as anti-inflammatory, hepatoprotective, and anti-carcinogenic activity against various cancer cell lines. Recently, we reported in-silico modeling coupled with in-vitro biological evaluations against mutant B-RAF melanoma cell lines as an initial investigation into the promising ability of cucurbitacins to target the Mitogen Activated Protein Kinase (MAPK) pathway. However, cucurbitacins are known for their multi-faceted biological effect by targeting multiple molecular targets, sometimes undesirably. The potential utility of cucurbitacins as potential drug candidates drew attention towards optimizing the selectivity, by analyzing important chemical functionalities responsible for binding to B-RAF via molecular modeling. This approach resulted in the identification of a side chain at C-17, possessing an a,�-unsaturated ketone at ring D, of a steroidal skeleton using a structure-based drug design approach. Three main sites were studied synthetically; 1) Assembling different functionalities at C-25 via aldol condensation reaction, 2) Thiophenol and azide conjugate addition reaction at C-24, 3) Trans, pseudo, and cis configurations of the B/C ring juncture of the steroidal skeleton. Twelve synthetic steps were carried out resulting in 20 novel intermediates and final analogs. These analogs were biologically screened using cytotoxicity and in-cell based ELISA assays, to show the potential of analogs possessing pseudo-cis configuration and the actual side chain of cucurbitacins to inhibit cell growth of A-375 cell lines with IC50 ranging from 12.20 -19.90 �M. The synthesized analogs also exhibited significant inhibition of phosphorylated ERK, induced by epidermal growth factor. These results offer a novel scaffold for targeting the MAPK pathway as a treatment for melanoma.

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

247th National Meeting (2014)

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