Novel silyl cyanocinnamic acid derivatives have been synthesized and evaluated as potential anticancer agents. In vitro studies reveal that lead derivatives 2a and 2b have enhanced cancer cell proliferation inhibition properties when compared to the parent monocarboxylate transporter (MCT) inhibitor cyano-hydroxycinnamic acid (CHC). Further, candidate compounds exhibit several-fold more potent MCT1 inhibition properties as determined by lactate-uptake studies, and these studies are supported by MCT homology modeling and computational inhibitor-docking studies. In vitro effects on glycolysis and mitochondrial metabolism also illustrate that the lead derivatives 2a and 2b lead to significant effects on both metabolic pathways. In vivo systemic toxicity and efficacy studies in colorectal cancer cell WiDr tumor xenograft demonstrate that candidate compounds are well tolerated and exhibit good single agent anticancer efficacy properties.
Bibliographical noteFunding Information:
This work was supported by University of Minnesota Duluth; Department of Defense Breast Cancer Research Proposal, Breakthrough Award (grant number W81XWH-15-1-0047, VRM); Department of Defense Breast Cancer Research Award (grant number W81XWH-15-1-0060, LRD), Whiteside Clinical Research Institute, Minnesota, and Randy Shaver Cancer Research and Community Fund, Minnesota.