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Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety.
Bioorg Med Chem. 2013 Oct 01; 21(19):5973-82.BM

Abstract

A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here.

Authors+Show Affiliations

Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi 835215, India. kalyansethi@gmail.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23965175

Citation

Sethi, Kalyan K., et al. "Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of the Human Carbonic Anhydrase Isoforms I, II, VII, IX and XII With Benzene Sulfonamides Incorporating 4,5,6,7-tetrabromophthalimide Moiety." Bioorganic & Medicinal Chemistry, vol. 21, no. 19, 2013, pp. 5973-82.
Sethi KK, Vullo D, Verma SM, et al. Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety. Bioorg Med Chem. 2013;21(19):5973-82.
Sethi, K. K., Vullo, D., Verma, S. M., Tanç, M., Carta, F., & Supuran, C. T. (2013). Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety. Bioorganic & Medicinal Chemistry, 21(19), 5973-82. https://doi.org/10.1016/j.bmc.2013.07.044
Sethi KK, et al. Carbonic Anhydrase Inhibitors: Synthesis and Inhibition of the Human Carbonic Anhydrase Isoforms I, II, VII, IX and XII With Benzene Sulfonamides Incorporating 4,5,6,7-tetrabromophthalimide Moiety. Bioorg Med Chem. 2013 Oct 1;21(19):5973-82. PubMed PMID: 23965175.
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TY - JOUR T1 - Carbonic anhydrase inhibitors: synthesis and inhibition of the human carbonic anhydrase isoforms I, II, VII, IX and XII with benzene sulfonamides incorporating 4,5,6,7-tetrabromophthalimide moiety. AU - Sethi,Kalyan K, AU - Vullo,Daniella, AU - Verma,Saurabh M, AU - Tanç,Muhammet, AU - Carta,Fabrizio, AU - Supuran,Claudiu T, Y1 - 2013/08/02/ PY - 2013/07/09/received PY - 2013/07/24/revised PY - 2013/07/25/accepted PY - 2013/8/23/entrez PY - 2013/8/24/pubmed PY - 2014/4/8/medline KW - 4,5,6,7-Tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide KW - ASN KW - AZM KW - BRZ KW - BZA KW - Benzenesulfonamide KW - CA KW - CAI KW - CLX KW - CNS KW - COX KW - DCP KW - DMSO KW - DZA KW - Docking KW - EZA KW - FT-IR KW - Fourier transform infrared KW - GLN KW - HIF KW - HIS KW - Human carbonic anhydrase inhibitors KW - IND KW - MZA KW - NMR KW - PDB KW - RMSD KW - SAR KW - SLP KW - Structure–activity relationship KW - THR KW - TLC KW - TPM KW - TRP KW - UV KW - VHL KW - VLX KW - XP KW - ZNS KW - Zn KW - acetazolamide KW - asparagine KW - benzolamide KW - brinzolamide KW - carbonic anhydrase KW - carbonic anhydrase inhibitor KW - celecoxib KW - central nervous system KW - cyclo-oxygenase enzyme KW - dibromophenamide KW - dimethyl sulfoxide KW - dorzolamide KW - ethoxzolamide KW - extra precision KW - glutamine KW - hCA KW - histidine KW - human carbonic anhydrase KW - hypoxia inducible factor KW - indisulam KW - mM KW - methazolamide KW - milimolar KW - nM KW - nanomolar KW - nuclear magnetic resonance KW - protein data bank KW - root mean square deviation KW - structure–activity relationship KW - sulpiride KW - thin layer chromatography KW - threonine KW - topiramate KW - tryptophan KW - ultraviolet KW - valdecoxib KW - von Hippel–Lindas protein KW - zinc KW - zonisamide SP - 5973 EP - 82 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 21 IS - 19 N2 - A series of 4,5,6,7-tetrabromo-1,3-dioxoisoindolin-2-yl benzenesulfonamide derivatives (compounds 1-8) was synthesized by reaction of benzene sulfonamide derivatives with 4,5,6,7-tetrabromophthalic anhydride moiety. These new sulfonamides were investigated as inhibitors of the zinc metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and more specifically against the human (h) cytosolic isoforms hCA I, II and VII and the transmembrane tumor-associated isoform hCA IX and XII. The new compounds were good hCA I inhibitors (Kis in the range of 143 to >10,000nM), but were moderately effective, as hCA II inhibitors (Kis of 47-190nM) and poor hCA VII inhibitors (Kis in the range of 54-175nM) compared to acetazolamide. The tumor-associated hCA IX was effectively inhibited with Kis ranging between 8.5 and 234nM and hCA XII with inhibition constants in the range of 6.1-197nM with high selectivity ratio. The structure-activity relationship (SAR) with this series of sulfonamides is straightforward, with the main features leading to good activity for each isoforms being established. The high sequence hCA alignment homology and molecular docking study of compounds was performed to rationalize the SAR reported over here. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/23965175/Carbonic_anhydrase_inhibitors:_synthesis_and_inhibition_of_the_human_carbonic_anhydrase_isoforms_I_II_VII_IX_and_XII_with_benzene_sulfonamides_incorporating_4567_tetrabromophthalimide_moiety_ DB - PRIME DP - Unbound Medicine ER -