2QP6

The crystal structure of the complex of hcaII with a bioreductive antitumor derivative

Summary for 2QP6

• Entry DOI: 10.2210/pdb2qp6/pdb
• Related: 1CA2 2QO8 2QOA
• Descriptor: Carbonic anhydrase 2, ZINC ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: carbonic anhydrase ii, lyase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P00918
• Total number of polymer chains: 1
• Total formula weight: 30017.65

Authors

D'Ambrosio, K.,De Simone, G. (deposition date: 2007-07-23, release date: 2008-06-03, Last modification date: 2023-08-30)

Primary citation

D'Ambrosio, K.,Vitale, R.M.,Dogne, J.M.,Masereel, B.,Innocenti, A.,Scozzafava, A.,De Simone, G.,Supuran, C.T.
Carbonic Anhydrase Inhibitors: Bioreductive Nitro-Containing Sulfonamides with Selectivity for Targeting the Tumor Associated Isoforms IX and XII.
J.Med.Chem., 51:3230-3237, 2008

PubMed 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.

PubMed: 18481843
DOI: 10.1021/jm800121c

Experimental method

X-RAY DIFFRACTION (1.45 Å)