2. Academic Validation
  3. Cucurbitacins inspired organic synthesis: Potential dual inhibitors targeting EGFR - MAPK pathway

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

  • Eur J Med Chem. 2019 Jul 1:173:294-304. doi: 10.1016/j.ejmech.2019.04.018.
Mater Mahnashi 1,  Sara M Elgazwi 2,  Mahmoud Salama Ahmed 3,  Fathi T Halaweish 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Najran University, Najran, P.O. 1988, Saudi Arabia.
  • 2 Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, 57006, USA.
  • 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, The British University in Egypt, El-Sherouk, Cairo, Egypt; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Mahmoud.salama@bue.edu.eg.
  • 4 Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, 57006, USA. Electronic address: fathi.halaweish@sdstate.edu.
PMID: 31022583 DOI: 10.1016/j.ejmech.2019.04.018
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.

Keywords

Biological oriented organic synthesis; Cucurbitacins; Diastereomers; EGFR; Estrone; MAPK pathway.

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