Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors

Abstract

Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on α-cyanocinnamic acid structural template. Candidate inhibitors 1–9 have been evaluated for in vitro cell proliferation against MCT1 and MCT4 expressing cancer cell lines. Potential MCT1 and MCT4 binding interactions of the lead compound 9 have been studied through homology modeling and molecular docking prediction. In vitro effects on extracellular flux via glycolysis and mitochondrial stress tests suggest that candidate compounds 3 and 9 disrupt glycolysis and OxPhos efficiently in MCT1 expressing colorectal adenocarcinoma WiDr and MCT4 expressing triple negative breast cancer MDA-MB-231 cells. Fluorescence microscopy analyses in these cells also indicate that compound 9 is internalized and concentrated near mitochondria. In vivo tumor growth inhibition studies in WiDr and MDA-MB-231 xenograft tumor models in mice indicate that the candidate compound 9 exhibits a significant single agent activity.

Development of Novel Silyl Cyanocinnamic Acid Derivatives as Metabolic Plasticity Inhibitors for Cancer Treatment

“…The silylated candidate compounds 2a and 2b were next evaluated for in vitro MCT1 transport inhibition properties using an L-[ 14 C]-lactate study on the MCT1 expressing RBE4 cell line as reported previously 18–20 . Both compounds 2a and 2b showed potent MCT1 inhibition with IC 50 values 408 and 97 nM, respectively (Table 2, Fig.…”

“…The non-silylated CHC derivatives 2c or 2d did not exhibit any cell proliferation inhibition properties reinforcing the importance of the TBDPS group in providing the cytotoxic properties. To evaluate the MCT1 inhibitory properties of synthesized compounds 2a-d , we performed a lactate uptake assay as previously described by us 18–20 . Again, both silylated derivatives 2a and 2b showed potent MCT 1 inhibition in low µM concentration compared to CHC which typically inhibits MCT1 function at or above 150 µM concentration.…”

“…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 . Similarly, N,N-dialkyl carboxy coumarins were also found by us 19 and others 21 to be highly potent toward lactate uptake inhibition in MCT1 expressing cells.…”

One-step radiosynthesis of the MCTs imaging agent [18F]FACH by aliphatic 18F-labelling of a methylsulfonate precursor containing an unprotected carboxylic acid group

“…1) 14 . Current studies have revealed that both, 1 and FACH, also possess high inhibition toward MCT4 (IC 50 : 11.0 nM for 1 and 6.5 nM for FACH) 14,15 , making these compounds even more attractive as drug and imaging probes. Accordingly, FACH was radiofluorinated by our group in order to develop the first 18 F-labelled MCTs inhibitor for PET imaging 14 .

Figure 1The potent MCT1 inhibitor 1 as lead compound and its corresponding fluorinated analogue FACH on the basis of the α -CHC core structure.

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“…Accordingly, FACH was radiofluorinated by our group in order to develop the first 18 F-labelled MCTs inhibitor for PET imaging 14 .

Figure 1The potent MCT1 inhibitor 1 as lead compound and its corresponding fluorinated analogue FACH on the basis of the α -CHC core structure. ( a ) Data published in 15 . ( b ) Data published in 14 .

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