Güzel Ozlen, Temperini Claudia, Innocenti Alessio, Scozzafava Andrea, Salman Aydin, Supuran Claudiu T
Istanbul University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 34116 Beyazit, Istanbul, Turkey.
Bioorg Med Chem Lett. 2008 Jan 1;18(1):152-8. doi: 10.1016/j.bmcl.2007.10.110. Epub 2007 Nov 4.
2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide was tested for its interaction with 12 carbonic anhydrase (CA, EC 4.2.1.1) isoforms in the search of compounds with good inhibitory activity against isozymes with medicinal chemistry applications, such as CA I, II, VA, VB, VII, IX, and XII among others. This sulfonamide is a potent inhibitor of CA I and II (K(I)s of 7.2-7.5 nM), a medium potency inhibitor of CA VII, IX, XII, and XIV, and a weak inhibitor against the other ubiquitous isoforms, making it thus a very interesting clinical candidate for situations in which a strong inhibition of CA I and II is needed. The crystal structure of the hCA II adduct of this sulfonamide revealed many favorable interactions between the inhibitor and the enzyme which explain its strong low nanomolar affinity for this isoform but may also be exploited for the design of effective inhibitors incorporating bicyclic moieties.
为了寻找对具有药物化学应用价值的同工酶（如CA I、II、VA、VB、VII、IX和XII等）具有良好抑制活性的化合物，对2-(肼基羰基)-3-苯基-1H-吲哚-5-磺酰胺与12种碳酸酐酶（CA，EC 4.2.1.1）同工型的相互作用进行了测试。这种磺酰胺是CA I和II的强效抑制剂（抑制常数K(I)为7.2 - 7.5 nM），是CA VII、IX、XII和XIV的中效抑制剂，对其他普遍存在的同工型是弱抑制剂，因此对于需要强烈抑制CA I和II的情况而言，它是一个非常有吸引力的临床候选药物。该磺酰胺与hCA II的加合物的晶体结构揭示了抑制剂与酶之间存在许多有利的相互作用，这解释了其对该同工型具有强的低纳摩尔亲和力，同时也可用于设计包含双环部分的有效抑制剂。
