New Pyridinium Salt Derivatives of 2-(Hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide as Selective Inhibitors of Tumour-Related Human Carbonic Anhydrase Isoforms IX and XII

GÜZEL AKDEMİR Ö., DEMİR YAZICI K., Vullo D., Supuran C. T., AKDEMİR A.

Anti-Cancer Agents in Medicinal Chemistry, cilt.22, sa.14, ss.2637-2646, 2022 (SCI-Expanded) identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 22 Sayı: 14
  • Basım Tarihi: 2022
  • Doi Numarası: 10.2174/1871520622666220207092123
  • Dergi Adı: Anti-Cancer Agents in Medicinal Chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Biotechnology Research Abstracts, Chemical Abstracts Core, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.2637-2646
  • Anahtar Kelimeler: anticancer agent, Carbonic anhydrase, hCA IX/XII, molecular dynamics simulations, molecular model-ling, pyridinium salt, sulfonamide, tumour-associated isoform
  • İstanbul Üniversitesi Adresli: Evet

Özet

© 2022 Bentham Science Publishers.Background: The positively charged membrane impermeant sulfonamides were evaluated as a remarkable class of carbonic anhydrase inhibitors (CAIs) previously. Without affecting the human carbonic anhydrase (hCA), cytosolic isoforms hCA I and II, inhibition of two membrane-associated isoforms hCA IX and XII especially over-expressed in hypoxic tumour cells, makes the pyridinium salt derivatives potent promising therapeutic agents. Objective: A novel series of tri, tetra, and cyclo-substituted pyridinium salt derivatives of the lead compound 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide has been prepared by using sixteen different pyrylium salts, for the search of selective inhibitors of transmembrane tumour-associated human carbonic anhydrase hCA IX and XII. Methods: Molecular modeling studies were carried out to understand and rationalize the in vitro enzyme inhibition data. Results: Six of the new compounds showed good inhibitory profiles with low nanomolar range (< 100 nM) against hCA IX/XII, and compound 5 showed excellent potency with Ki values lower than 10 nM. In addition, molecular mod-elling studies have presented the possible binding modes of the ligands. Conclusion: Most of the compounds displayed potent inhibitory activity against the tumor-associated hCA IX and XII in the low nanomolar range and selectivity over the off-targeted isoforms hCA I and II. Due to their cationic structure and membrane-impermeant behavior, it is also expected to maximize the selectivity over cytosolic isoforms hCA I/II while inhibiting tumor overexpressed isoforms hCA XI/XII of new compounds in in vivo conditions.