Eskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
Bioorg Med Chem. 2012 Apr 1;20(7):2392-404. doi: 10.1016/j.bmc.2012.01.052. Epub 2012 Feb 9.
A library of 32 novel glycoconjugate thiourea-bridged benzene sulfonamides have been synthesized from the reaction of glycosyl isothiocyanates with a panel of simple benzene sulfonamides comprising either a free amine or hydrazide. All compounds were investigated for their ability to inhibit the enzymatic activity of five human carbonic anhydrase (hCA) isozymes: hCA I, II and membrane-associated isozymes IX, XII and XIV. A physicochemical feature of the free sugar thioureido glycoconjugates was high water solubility (> 20 mg/mL), as well many of these compounds exhibited a desirable potency and CA isozyme selectivity profile. From this library several inhibitors displayed excellent potency-selectivity profiles for transmembrane anchored CAs over off-target CA I and II. These molecules provide potential dual-acting candidates for the development of inhibitors that target the extracellular CAs (IX, XII and XIV)-either directly as free sugars (membrane impermeable) or indirectly as acetylated prodrugs, becoming free sugars upon esterase hydrolysis.
从糖基异硫氰酸酯与一系列简单苯磺酰胺（包括游离胺或酰肼）的反应中，合成了 32 种新型糖基硫脲桥联苯磺酰胺库。所有化合物均被用于研究其抑制五种人碳酸酐酶（hCA）同工酶：hCA I、II 和膜结合同工酶 IX、XII 和 XIV 的酶活性的能力。游离糖硫脲糖缀合物的理化特征是高水溶性（>20mg/mL），并且许多这些化合物表现出令人满意的效力和 CA 同工酶选择性特征。从该文库中，一些抑制剂对跨膜锚定 CA 表现出极好的效力选择性，而对非靶标 CA I 和 II 则没有活性。这些分子为开发抑制剂提供了潜在的双重作用候选物，这些抑制剂可以靶向细胞外 CA（IX、XII 和 XIV）-直接作为游离糖（膜不可渗透）或间接作为乙酰化前药，通过酯酶水解成为游离糖。
