【文章名】Carbonic anhydrase inhibitors: bioreductive nitro-containing sulfonamides with selectivity for targeting the tumor associated isoforms IX and XII.
[摘要]：2-Substituted-5-nitro-benzenesulfonamides incorporating a large variety of secondary/tertiary amines were explored as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), with the aim of designing bioreductive inhibitors targeting the hypoxia overexpressed, tumor-assocd. isoenzymes. The compds. were ineffective inhibitors of the cytosolic isoform I, showed a better inhibition of the physiol. relevant CA II (KIs of 8.8-4975 nM), and strongly inhibited the tumor-assocd. CA IX and XII (KIs of 5.4-653 nM). Some of these compds. showed excellent selectivity ratios for the inhibition of the tumor-assocd. isoenzymes over the cytosolic ones (in the range of 10-1395). The X-ray crystal structure of the adduct of hCA II with the lead mol. 2-chloro-5-nitro-benzenesulfonamide as well as mol. modeling studies for interaction with hCA IX afforded a better understanding of factors governing the discrimination of the two isoforms for this type of bioreductive compd. targeting specifically hypoxic tumors.
