ABSTRACT
As an oncometabolite, lactate plays a very important role in tumor proliferation, metastasis, angiogenesis, immune escape and other tumor biological functions. Pharmacological inhibition oflactate transport has been viewed as a promising therapeutic strategy to target a range of human cancers. In this study, a series of new coumarin-3-carboxylic acid derivatives 5a-t and 9a-b were synthesized and evaluated as lactate transport inhibitors. Their cytotoxic activity has been tested against three cell lines high-expressing and low-expressing monocarboxylate transporter 1 (MCT1) which acts as the main carrier for lactate. Compound 5c-e, 5g-i and 5m-o showed significant cytotoxicity and good selectivity against Hela and HCT116 cell lines with high MCT1 expression. Notably, coumarin-3-hydrazide 5o, the lead molecule with the most potent cytotoxic activity, exhibitedsignificant anti-proliferationandapoptosisinductioneffects. Further studies revealed that compound 5o decreased the expression level of target MCT1, and suppressed the energetic metabolism of Hela and HCT116 cells byremarkably reducing glucoseconsumptionandlactate production. Additionally, compound 5o induced intracellular lactate accumulation and inhibited lactate uptake, which implied that it blocked lactate transport via MCT1. These results indicate a good start point for the development of lactate transport inhibitors as new anticancer agents.
