(1S, 2E, 4S, 7E, 11E)-2, 7, 11-Cembratriene-4, 6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies. Issue 22 (15th November 2016)

• Record Type: Journal Article
• Authors: Ebrahim, Hassan Y.; Mohyeldin, Mohamed M.; Hailat, Mohammad M.; El Sayed, Khalid A.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 22(2016)
• Page Start: 5748
• Page End: 5761
• Publication Date: 2016-11-15
• Subjects: Breast cancer -- c-Met -- Hit-to-lead -- Rational design -- Semisynthesis -- Tobacco cembranoids 1; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.09.032
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: (1 S, 2 E, 4 S, 6 R, 7 E, 11 E )-2, 7, 11-Cembratriene-4, 6-diol (1 ) and its 4- epi -analog (2 ) are the cembranoid precursors to several key flavor ingredients in most Nicotiana (tobacco) species. Nearly 40–60% of1 and2 are purposely degraded during the commercial tobacco fermentation. However, 1 and2 display promising bioactivities, including anticancer. Breast cancer is the most diagnosed cancer in women and ranked second female disease killer. The receptor tyrosine kinase c-Met correlates with aggressiveness of certain breast cancer phenotypes and thus considered a valid therapeutic target. This study reports the discovery and optimization of the tobacco-based cembranoid1 as a novel c-Met inhibitory scaffold using combined structure- and ligand-based approaches.1 displayed antiproliferative, anti-migratory and anti-invasive effects against the c-Met overexpressing MDA-MB-231 breast cancer cells at moderate μM concentrations. The Z′-LYTE kinase platform and Western blot analysis identified c-Met as a potential macromolecular target. Rationally designed carbamate analogs were proposed to probe additional targeted c-Met interactions and improve the cellular potency. The 6-phenyl carbamate3 showed enhanced c-Met inhibitory activity. Structure–activity relationships of different substituents on the3 's phenyl moiety were studied. The most active analog20 showed potent in vitro anticancer activity against the MDA-MB-231 breast cancer cells at low μM concentrations, with minimal toxicity on the non-tumorigenic MCF-10A mammary epithelial cells. Cembranoid20 potently inhibited the c-Met catalytic activity in Z′-LYTE kinase assay and various cellular c-Met-driven signaling pathways. Furthermore, 20 displayed a robust antitumor activity in a breast cancer xenograft athymic mouse model and thus promoted to the lead rank. Cembranoids are novel c-Met inhibitors appropriate for future use to control c-Met dependent malignancies.