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J Med Chem. 2008 Jun 12;51(11):3230-7. doi: 10.1021/jm800121c. Epub 2008 May 16.

Carbonic anhydrase inhibitors: bioreductive nitro-containing sulfonamides with selectivity for targeting the tumor associated isoforms IX and XII.

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  • 1Istituto di Biostrutture e Bioimmagini-CNR, Napoli, Italy.

Abstract

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-associated isozymes. The compounds were ineffective inhibitors of the cytosolic isoform I, showed a better inhibition of the physiologically relevant CA II (KIs of 8.8-4975 nM), and strongly inhibited the tumor-associated CA IX and XII (KIs of 5.4-653 nM). Some of these compounds showed excellent selectivity ratios for the inhibition of the tumor-associated isozymes over the cytosolic ones (in the range of 10-1395). The X-ray crystal structure of the adduct of hCA II with the lead molecule 2-chloro-5-nitro-benzenesulfonamide as well as molecular 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 compound targeting specifically hypoxic tumors.

PMID:
18481843
DOI:
10.1021/jm800121c
[PubMed - indexed for MEDLINE]
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