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首页> 外文期刊>Bioorganic and Medicinal Chemistry Letters >Carbonic anhydrase inhibitors: inhibition of the human isozymes I, II, VA, and IX with a library of substituted difluoromethanesulfonamides.
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Carbonic anhydrase inhibitors: inhibition of the human isozymes I, II, VA, and IX with a library of substituted difluoromethanesulfonamides.

机译：碳酸酐酶抑制剂：用取代的二氟甲磺酰胺库抑制人同工酶I，II，VA和IX。

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摘要

An inhibition study of the human cytosolic isozymes I, and II, the mitochondrial isoform VA, and the tumor-associated, transmembrane isozyme IX of carbonic anhydrase (CA, EC 4.2.1.1) with a library of aromatic/heteroaromatic/polycyclic difluoromethanesulfonamides is reported. Most of the inhibitors were derivatives of benzenedifluoromethanesulfonamide incorporating substituted-phenyl moieties, or were methylsulfonamide and difluoromethyl-sulfonamide derivatives of the sulfamates COUMATE and EMATE, respectively. Except for the methylsulfonamide-COUMATE derivative which behaved as a potent CA II inhibitor (K(I) of 32nM), these sulfonamides were moderate inhibitors of all isozymes, with inhibition constants in the range of 96-5200nM against hCA I, of 80-670nM against hCA II, and of 195-9280nM against hCA IX, respectively. Remarkably, some derivatives, such as 3-bromophenyl-difluoromethanesulfonamide, showed a trend to selectively inhibit the mitochondrial isoform CA VA, showing selectivity ratios for inhibiting CA VA over CA II of 3.53; over CA I of 6.84 and over CA IX of 9.34, respectively, although it is a moderate inhibitor (K(I) of 160nM). Some of these derivatives may be considered as leads for the design of isozyme selective CA inhibitors targeting the mitochondrial isozyme CA VA, with potential use as anti-obesity agents.
机译：有人用芳香族/杂芳香族/多环二氟甲烷磺酰胺库对人胞质同工酶I和II，线粒体同工酶VA和与肿瘤相关的碳酸酐酶跨膜同工酶IX（CA，EC 4.2.1.1）进行了抑制研究。 。大多数抑制剂是结合有取代苯基部分的苯二氟甲磺酰胺的衍生物，或者分别是氨基磺酸盐COUMATE和EMATE的甲基磺酰胺和二氟甲基磺酰胺衍生物。除了可作为有效的CA II抑制剂的甲基磺酰胺-库姆酯衍生物（K（I）为32nM）外，这些磺酰胺均为所有同功酶的中度抑制剂，对hCA I的抑制常数在96-5200nM范围内，为80-针对hCA II的抗体为670nM，针对hCA IX的抗体为195-9280nM。值得注意的是，某些衍生物，例如3-溴苯基-二氟甲磺酰胺，显示出选择性抑制线粒体同种型CA VA的趋势，相对于CA II而言，抑制CA VA的选择性比为3.53;虽然它是中度抑制剂（K（I）为160nM），但分别高于6.84的CA I和9.34的CA IX。这些衍生物中的一些可以被认为是设计针对线粒体同工酶CA VA的同工酶选择性CA抑制剂的先导，有可能用作抗肥胖药。

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