Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: In vitro and in vivo studies as potential anticancer agents. Issue 14 (15th July 2016)

• Record Type: Journal Article
• Authors: Gurrapu, Shirisha; Jonnalagadda, Sravan K.; Alam, Mohammad A.; Ronayne, Conor T.; Nelson, Grady L.; Solano, Lucas N.; Lueth, Erica A.; Drewes, Lester R.; Mereddy, Venkatram R.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 26:Issue 14(2016)
• Page Start: 3282
• Page End: 3286
• Publication Date: 2016-07-15
• Subjects: N, N-Dialkyl carboxy coumarin -- Tumor glycolysis -- Monocarboxylate transporter 1 -- MCT -- Glioblastoma -- GL261-luc2 -- Triple negative breast cancer -- MDA-MB-231; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.05.054
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Novel N, N -dialkyl carboxy coumarins have been synthesized as potential anticancer agents via inhibition of monocarboxylate transporter 1 (MCT1). These coumarin carboxylic acids have been evaluated for their in vitro MCT1 inhibition, MTT cancer cell viability, bidirectional Caco-2 cell permeability, and stability in human and liver microsomes. These results indicate that one of the lead candidate compounds4a has good absorption, metabolic stability, and a low drug efflux ratio. Systemic toxicity studies with lead compound4a in healthy mice demonstrate that this inhibitor is well tolerated based on zero animal mortality and normal body weight gains compared to the control group. In vivo tumor growth inhibition studies in mice show that the candidate compound4a exhibits significant single agent activity in MCT1 expressing GL261-luc2 syngraft model but doesn't show significant activity in MCT4 expressing MDA-MB-231 xenograft model, indicating the selectivity of4a for MCT1 expressing tumors.