Abstract
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.
Highlights
Increased glycolysis results in the generation of byproducts such as lactic acid leading to an initial decrease in the internal pH; compensated by the elevated expression of monocarboxylate transporters (MCTs) and other transporters that efflux the acidic components and decrease the external pH7,8
Encouraged by significant cell proliferation inhibition and potent MCT1 inhibition properties of TBDPS-cyanohydroxycinnamic acid (CHC) 2a and Ex-TBDPS-CHC 2b, we evaluated these candidate compounds for their effect on metabolic profiles in vitro using a Seahorse XFe96 analyzer
Oxygen, and nutrients throughout the tumor vary and glycolysis and oxidative phosphorylation (OxPhos) machinery exhibit differential expression patterns depending on the microenvironment of the cells[9,10,12]
Summary
Increased glycolysis results in the generation of byproducts such as lactic acid leading to an initial decrease in the internal pH; compensated by the elevated expression of monocarboxylate transporters (MCTs) and other transporters that efflux the acidic components and decrease the external pH7,8. Increasing the efficacy of CHC-based compounds to simultaneously target TCA cycle and OxPhos constitute novel chemotherapeutic strategy In this regard, we have replaced the 4-hydroxy group in CHC with N,N-dialkyl/aryl groups that has resulted in low nanomolar potency towards lactate uptake in both MCT1 and MCT4 expressing cell lines[18,20]. We envisioned that introduction of an acid stable TBDPS ether on CHC phenolic hydroxyl group would increase its lipophilicity, metabolic stability, and ability to influence mitochondrial function while retaining MCT inhibitory characteristics In this regard, we synthesized and evaluated novel silyl-CHC compounds for their in vitro MCT1 inhibitory properties, in vitro effects on cancer cell proliferation and metabolism, and in vivo safety and efficacy in a WiDr tumor xenograft model. The lead candidate compounds exhibited enhanced MCT1 and cancer cell proliferation inhibition properties, led to glycolysis and mitochondrial dysfunction, and showed significant in vivo tumor growth inhibitions
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