Fragment-based drug discovery of carbonic anhydrase II inhibitors by dynamic combinatorial chemistry utilizing alkene cross metathesis

摘要

A fragment-based drug discovery approach to the synthesis and identification of small molecule inhibitors of bovine carbonic anhydrase II (bCA II) is described. The classical bCA II recognition fragment is an aromatic sulfonamide (ArSO2NH2) moiety. This fragment was incorporated into a scaffold building block, which was subsequently derivatized by dynamic combinatorial chemistry utilizing alkene cross metathesis as the reversible reaction. Screening against bCA II was then carried out and the results allowed determination of the relative bCA II binding affinities of the cross metathesis products that contained the ArSO2NH2 fragment. A bCA II competitive binding assay validated these results with a representative number of pure compounds. The results for screening, without prior isolation of the active constituent, were in full agreement with those obtained for equilibrium dissociation constants (Ki's) of pure compounds. Some of these compounds exhibited Ki's in the low nanomolar range. Heterogeneous catalysis was shown to be very effective in this drug discovery application of dynamic combinatorial chemistry.