Title: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
Volume: 22
Issue: 14
Author(s): Özlen Güzel-Akdemir, Kübra Demir-Yazıcı, Daniela Vullo, Claudiu T. Supuran and Atilla Akdemir*
Affiliation:
- Computer-aided Drug Discovery Laboratory, Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey
Keywords:
Carbonic anhydrase, tumour-associated isoform, hCA IX/XII, sulfonamide, pyridinium salt, anticancer agent, molecular modelling, molecular dynamics simulations.
Abstract:
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 overexpressed
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 modelling
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.