Cucurbitacins inspired organic synthesis: Potential dual inhibitors targeting EGFR – MAPK pathway

Mater Mahnashi, Sara M. Elgazwi, Mahmoud Salama Ahmed, Fathi T. Halaweish

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)294-304
Number of pages11
JournalEuropean Journal of Medicinal Chemistry
Volume173
DOIs
StatePublished - Jul 1 2019

Keywords

  • Biological oriented organic synthesis
  • Cucurbitacins
  • Diastereomers
  • EGFR
  • Estrone
  • MAPK pathway

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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