CRCU

Chemical Research in Chinese Universities ›› 2004, Vol. 20 ›› Issue (3): 334-337.

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Synthesis and Characterization of A Small Molecule CFTR Chloride Channel Inhibitor

HE Cheng-yan1,3, ZHANG Heng-jun2, SU Zhong-min2, ZHOU Jin-song3, YANG Hong1, MA Tong-hui1   

  1. 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
  • Received:2003-12-29 Online:2004-06-24 Published:2011-08-06
  • Supported by:

    Supported by the Start-up Fund for Returned Overseas Scholars from Northeast Normal University, National Science Fund for Distinguished Young Scholars(No.30325011), Distinguished Young Scholars Fund of Jilin Province(No.20030112), and the National Science Foundation of Jilin Province(No.20010548 and 20030708).

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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.

Key words: Cystic fibrosis transmembrane conductance regulator(CFTR), CFTR chloride channel, Fisher rat thyroid(FRT), Yellow fluorescent protein(YFP), Diarrhea, Cystic fibrosis