Research Article

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

Author(s):

Özlen Güzel-Akdemir, Kübra Demir-Yazıcı, Daniela Vullo, Claudiu T. Supuran and Atilla Akdemir*   Pages 2637 - 2646 ( 10 )

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 K_i 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.

Keywords:

Carbonic anhydrase, tumour-associated isoform, hCA IX/XII, sulfonamide, pyridinium salt, anticancer agent, molecular modelling, molecular dynamics simulations.

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