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

Mater Mahnashi; Sara M Elgazwi; Mahmoud Salama Ahmed; Fathi T Halaweish

doi:10.1016/j.ejmech.2019.04.018

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. Epub 2019 Apr 16.

Authors

Mater Mahnashi¹, Sara M Elgazwi², Mahmoud Salama Ahmed³, Fathi T Halaweish⁴

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Cell Movement / drug effects
Cell Proliferation / drug effects
Cucurbitacins / chemical synthesis
Cucurbitacins / chemistry
Cucurbitacins / pharmacology*
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / metabolism
Hep G2 Cells
Humans
MAP Kinase Signaling System / drug effects*
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Cucurbitacins
EGFR protein, human
ErbB Receptors