2qp6
The crystal structure of the complex of hcaII with a bioreductive antitumor derivative
OverviewOverview
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 ( K Is of 8.8-4975 nM), and strongly inhibited the tumor-associated CA IX and XII ( K Is 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.
About this StructureAbout this Structure
2QP6 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Carbonic Anhydrase Inhibitors: Bioreductive Nitro-Containing Sulfonamides with Selectivity for Targeting the Tumor Associated Isoforms IX and XII., D'Ambrosio K, Vitale RM, Dogne JM, Masereel B, Innocenti A, Scozzafava A, De Simone G, Supuran CT, J Med Chem. 2008 May 16;. PMID:18481843 Page seeded by OCA on Wed Jun 4 09:52:02 2008