title: Structural optimization and biological screening of a steroidal scaffold possessing cucurbitacin-like functionalities as B-Raf inhibitors.
abstract: Inhibition of the mitogen-activated protein kinase (MAPK) pathway by targeting the commonly occurring mutated B-Raf in melanoma has become a practical method for the development of drugs and drug candidates. In order to expand upon the currently reported structural scaffolds used to target the MAPK pathway, molecular docking studies led to the installation an α,β-unsaturated ketone side chain, related to the cucurbitacin class of natural products, on to an estrone core via an aldol condensation reaction, along with installation of the Δ(9,11) olefin to assemble what has been defined as a pseudo-cis configuration at the B/C ring juncture. Combination of these cucurbitacin-like features resulted in a compound with an enhanced biological profile against the A-375 mutant B-Raf cell line, in regards to their cytotoxicity and inhibitory activity toward phosphorylated extracellular-signal-regulated kinase (ERK).
authors.affiliation: Department of Chemistry & Biochemistry, South Dakota State University, Box 2202, Brookings, SD 57007 (USA).
authors.forename: Mahmoud S
authors.initials: MS
authors.lastname: Ahmed
authors.forename: Lucas C
authors.initials: LC
authors.lastname: Kopel
authors.forename: Fathi T
authors.initials: FT
authors.lastname: Halaweish
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001688:Biological Products / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D054728:Cucurbitacins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D054728:Cucurbitacins; D048493:Proto-Oncogene Proteins B-raf
keywords: B-Raf; anticancer agents; cucurbitacins; kinases; molecular modeling; natural products