The “tail
approach” has become a milestone in human
carbonic anhydrase inhibitor (hCAI) design for various therapeutics,
including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic
division of hCAs active site, several subpockets have been identified
at the middle/outer active sites rim, which could be targeted to increase
the CAI isoform selectivity. This postulate is explored here by three-tailed
benzenesulfonamide CAIs (
TTI
) to fully exploit such amino
acid differences among hCAs. In this proof-of-concept study, an extensive
structure–activity relationship (SAR) study was carried out
with 32 such benzenesulfonamides differing in tails combination that
were assayed for hCAs I, II, IV, and XII inhibition. A structural
study was undertaken by X-ray crystallography and
in silico
tools to assess the ligand/target interaction mode. The most active
and selective inhibitors against isoforms implicated in glaucoma were
assessed in a rabbit model of the disease achieving an intraocular
pressure-lowering action comparable to the clinically used dorzolamide.
Bile acids have been shown to inhibit human (h) carbonic anhydrases (CA, EC 4.2.1.1) along the gastrointestinal tract, including hCA II. The elucidation of the hormonal inhibition mechanism of the bile acid cholate to hCA II was provided in 2014 by X-ray crystallography. Herein, we extend the inhibition study to a wealth of steroids against four relevant hCA isoforms. Steroids displaying pendants and functional groups of the carboxylate, phenolic or sulfonate types appended at the tetracyclic ring were shown to inhibit the cytosolic CA II and the tumor-associated, transmembrane CA IX in a medium micromolar range (38.9-89.9 µM). Docking studies displayed the different chemotypes CA inhibition mechanisms. Molecular dynamics (MD) gave insights on the stability over time of hyocholic acid binding to CA II.
The synthesis and characterization of two new sets of arylsulfonehydrazone benzenesulfonamides (4a-4i with phenyl tail and 4j-4q with tolyl tail) are reported. The compounds were designed according to a dual-tails approach to modulate the interactions of the ligands portions at the outer rim of both hydrophobic and hydrophilic active site halves of human isoforms of carbonic anhydrase (CA, EC 4.2.1.1). The synthesized sulfonamides were evaluated in vitro for their inhibitory activity against the following human (h) isoforms, hCA I, II, IV and IX. With the latter being a validated anticancer drug target and a marker of tumor hypoxia, attractive results arose from the Compounds' inhibitory screening in terms of potency and selectivity. Indeed, whereas the first subset of compounds 4a-4i exhibited great efficacy in inhibiting both the ubiquitous, off-target hCA II (K I s 9.5e172.0 nM) and hCA IX (K I s 7.5e131.5 nM), the second subset of tolyl-bearing derivatives 4j-4q were shown to possess a selective hCA IX inhibitory action over isoforms I, II and IV. The most selective compounds 4l and 4n were further screened for their in vitro cytotoxic activity against MCF-7 and MDA-MB-231 cancer cell lines under hypoxic conditions. The selective IX/II inhibitory trend of 4j-4q compared to those of compounds 4a-4i was unveiled by docking studies. Further exploration of these molecules could be useful for the development of novel antitumor agents with a selective CA inhibitory mechanism.
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