Synthesis and Characterization of A Small Molecule CFTR Chloride Channel Inhibitor |
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Authors: | HE Cheng-Yan ZHANG Heng-Jun SU Zhong-min ZHOU Jin-song YANG Hong MA Tong-Hui |
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Affiliation: | 1. Membrane Channel Research Laboratory, Northeast Normal University, Changchun 130024, P. R. China; 2. Institute of Functional Material Chemistry, Northeast Normal University, Changchun 130024, P. R. China; 3. Department of Laboratory Medicine, China-Japan Union Hospital, Jilin University, Changchun 130033, P. R. China |
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Abstract: | A thiazolidinone CFTR inhibitor(CFTRinh-172) was synthesized by a three-step procedure with trifluromethylaniline as the starting material. The synthesized CFTR inhibitor was characterized structurally by means of 1H NMR and functionally in a CFTR-expressing cell line FRT/hCFTR/EYFP-H148Q by both fluorescent and electrophysiological methods. A large amount(100 g) of high-quality small molecule thiazolidinone CFTR chloride channel inhibitor, CFTRinh-172, can be produced with this simple three-step synthetic procedure. The structure of the final product 2-thioxo-3-(3-trifluromethylphenyl)-5-[4-carboxyphenyl-methylene]-4-thiazolidinone was confirmed by 1H NMR. The overall yield was 58% with a purity over 99% as analyzed by HPLC. The synthesized CFTRinh-172 specifically inhibited CFTR chloride channel function in a cell-based fluorescence assay(Kd≈1.5 μmol/L) and in a Ussing chamber-based short-circuit current assay(Kd≈0.2 μmol/L), indicating better quality than that of the commercial combinatorial compound. The synthesized inhibitor is nontoxic to cultured cells at a high concentration and to mouse at a high dose. The synthetic procedure developed here can be used to produce a large amount of the high-quality CFTRinh-172 suitable for antidiarrheal studies and for creation of cystic fibrosis models in large animals. The procedure can be used to synthesize radiolabled CFTRinh-172 for in vivo pharmacokinetics studies. |
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Keywords: | Cystic fibrosis transmembrane conductance regulator(CFTR) CFTR chloride channel Fisher rat thyroid(FRT) Yellow fluorescent protein(YFP) Diarrhea Cystic fibrosis |
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