title: Coumarin carboxylic acids as monocarboxylate transporter 1 inhibitors: In vitro and in vivo studies as potential anticancer agents.
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 compounds 4a has good absorption, metabolic stability, and a low drug efflux ratio. Systemic toxicity studies with lead compound 4a 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 compound 4a 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 of 4a for MCT1 expressing tumors.
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Shirisha
authors.initials: S
authors.lastname: Gurrapu
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Sravan K
authors.initials: SK
authors.lastname: Jonnalagadda
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Alam
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Conor T
authors.initials: CT
authors.lastname: Ronayne
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Grady L
authors.initials: GL
authors.lastname: Nelson
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States.
authors.forename: Lucas N
authors.initials: LN
authors.lastname: Solano
authors.affiliation: Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Lueth
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States; Department of Biomedical Sciences, Medical School Duluth, University of Minnesota Duluth, MN 55812, United States.
authors.forename: Lester R
authors.initials: LR
authors.lastname: Drewes
authors.affiliation: Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, United States; Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, United States; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, United States. Electronic address: vmereddy@d.umn.edu.
authors.forename: Venkatram R
authors.initials: VR
authors.lastname: Mereddy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D015394:Molecular Structure; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D003374:Coumarins; D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D000099233:Monocarboxylate Transport Protein 1
keywords: GL261-luc2; Glioblastoma; MCT; MDA-MB-231; Monocarboxylate transporter 1; N,N-Dialkyl carboxy coumarin; Triple negative breast cancer; Tumor glycolysis