o-Benzenedisulfonimido-sulfonamides are potent inhibitors of the tumor-associated carbonic anhydrase isoforms CA IX and CA XII

Guzel-Akdemir O., Akdemir A., Işık S., Vullo D., Supuran C. T.

BIOORGANIC & MEDICINAL CHEMISTRY, cilt.21, ss.1386-1391, 2013 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 21
  • Basım Tarihi: 2013
  • Doi Numarası: 10.1016/j.bmc.2012.12.037
  • Dergi Adı: BIOORGANIC & MEDICINAL CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1386-1391
  • Anahtar Kelimeler: Carbonic anhydrase, Cytosolic isoforms I and II, Tumor-associated isoforms IX and XII, o-Benzenedisulfonimide, Sulfonamide, X-RAY, CRYSTAL-STRUCTURE, ISOZYME-II, DOMAIN
  • İstanbul Üniversitesi Adresli: Evet

Özet

By using phthalimido-substituted aromatic sufonamides as lead molecules, a series of new sulfonamides incorporating ortho-benzenedisulfonimide moieties have been synthesized and tested against the human (h) cytosolic carbonic anhydrase (CA, EC 4.2.1.1) isozymes hCA I and hCA II and the transmembrane, tumor-associated isozymes hCA IX and hCA XII. All these compounds showed K-i values lower than 100 nM and many of them showed better K(i)s than the reference compound acetazolamide, a clinically used sulfonamide. The tumor-associated isozymes were better inhibited than the cytosolic ones. A molecular docking within the active site of some CA isoforms, such as hCA I, explained these findings, as the benzenedisulfonimide moiety makes favorable interactions (hydrogen bonds) with amino acid residues involved in binding of inhibitors, such as Gln92, His67, and His64. (C) 2012 Elsevier Ltd. All rights reserved.