Carbonic Anhydrase Inhibitors Developed Through ‘Click Tailing’

Marie      Lopez; Adam      J. Salmon; Claudiu      T. Supuran; Sally-Ann      Poulsen

doi:10.2174/138161210793429869

Abstract

In recent years there has been renewed activity in the literature concerning the 1,3-dipolar cycloaddition reaction (1,3-DCR) of organic azides (R-N3) with alkynes (R´ C≡CH)to form 1,2,3-triazoles, i.e. the Huisgen synthesis. The use of catalytic Cu(I) leads to a dramatic rate enhancement (up to 107-fold) and exclusive synthesis of the 1,4-disubstituted 1,2,3-triazole product. The reaction, now referred to as the copper-catalyzed azide-alkyne cycloaddition (CuAAC), meets the stringent criteria of a click-reaction in that it is modular, wide in scope, high yielding, has no byproducts, operates in water at ambient temperature, product purification is simple and the starting materials are readily available. The 1,3-DCR reaction has rapidly become the premier click chemistry reaction with applications spanning modern chemistry disciplines, including medicinal chemistry. Recently the ‘tail’ approach initiative for the development of carbonic anhydrase inhibitors (CAIs) has been combined with the synthetic versatility of click chemistry. This has proven a powerful combination leading to the synthesis of CAIs with useful biopharmaceutical properties and activities. This review will discuss complementary and contrasting applications that have utilized ‘click tailing’ for the development of CAIs. Applications encompass i) medicinal chemistry and drug discovery; ii) radiopharmaceutical development of positron emission topography (PET) chemical probes; and iii) in situ click chemistry.

Keywords: Carbonic anhydrase, click chemistry, hypoxia, CA IX, glycoconjugates, sulfonamide, medicinal chemistry, metallocene, 1, 3-dipolar cycloaddition reaction (1, 3-DCR), organic azides (R-N3), Huisgen synthesis, copper-catalyzed azide-alkyne cycloaddition (CuAAC), carbonic anhydrase inhibitors (CAIs), sulfonamide moiety, sulfonamide anion (SO2NH), Protein Data Bank (PDB), Isosteres, sulfamates, acetazolamide, ethoxzolamide, dichlorophenamide, tail approach, structure-property relationships (SPR), triazole, Click Tailing, solid tumor, glioblastoma, lipophilicity, pharmacophore, heteroaryl sulfonamides, azido sugars, O-glycoside linkage, S-linked glycosyltriazoles, effective permeability, Metallocenes Targeting Tumor, organometallic fragment, ferrocifen, tamoxifen, ethnylferrocene, ethynylruthenocene, lipogenesis, zonisamide (ZNS), topiramate (TPM), hypoxic tumor, dissociation constants (Kds), radionuclide, Hypoxia-inducible factor, short hairpin RNA, calculated Log P, Parallel artificial membrane permeability assay