Abstract
Natural products have been known as a fundamental source for drug discovery leading to the evolution of Biological Oriented Organic Synthesis (BIOS) approach to assemble natural product mimics. Herein, a series of Cucurbitacin inspired estrone analogs was assembled to generate 18 novel synthesized analogs via installation of double bond across C-16/C-17 positions of estrone scaffold and diastereomeric separation of (R) and (S) at C-20. This was followed by biological screening against HEPG-2 cell lines to exhibit anti-proliferative activity ranging from IC50 0.70–32 μM. Two analogs (MMA-102 and MMA-132) were chosen for further biological elucidation to exhibit dual inhibitory mechanism against the phosphorylating pathways of EGFR and MAPK (RAS/RAF/MEK/ERK) pathways. Both of MMA-102 and MMA-132 showed cell cycle arrest with elevated levels of apoptotic parameters. Molecular modeling simulations suggested the potential of MMA-102 and MMA-132 to compete with ATP within the catalytic binding domains of EGFR and MAPK pathway.
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•18 novel cucurbitacin inspired estrone analogs were designed and synthesized.•Diastereomeric separation resulted in two promising analogs.•MMA-102 and MMA-132 showed dual inhibitory mechanism against EGFR and MAPK pathway.