Methyl 2-Halo-4-Substituted-5-Sulfamoyl-Benzoates as High Affinity and Selective Inhibitors of Carbonic Anhydrase IX

Abstract

Among the twelve catalytically active carbonic anhydrase isozymes present in the human body, the CAIX is highly overexpressed in various solid tumors. The enzyme acidifies the tumor microenvironment enabling invasion and metastatic processes. Therefore, many attempts have been made to design chemical compounds that would exhibit high affinity and selective binding to CAIX over the remaining eleven catalytically active CA isozymes to limit undesired side effects. It has been postulated that such drugs may have anticancer properties and could be used in tumor treatment. Here we have designed a series of compounds, methyl 5-sulfamoyl-benzoates, which bear a primary sulfonamide group, a well-known marker of CA inhibitors, and determined their affinities for all twelve CA isozymes. Variations of substituents on the benzenesulfonamide ring led to compound 4b, which exhibited an extremely high observed binding affinity to CAIX; the Kd was 0.12 nM. The intrinsic dissociation constant, where the binding-linked protonation reactions have been subtracted, reached 0.08 pM. The compound also exhibited more than 100-fold selectivity over the remaining CA isozymes. The X-ray crystallographic structure of compound 3b bound to CAIX showed the structural position, while several structures of compounds bound to other CA isozymes showed structural reasons for compound selectivity towards CAIX. Since this series of compounds possess physicochemical properties suitable for drugs, they may be developed for anticancer therapeutic purposes.

Structure and Dynamics of the Isozymes II and IX of Human Carbonic Anhydrase

“…The shape of the ligand therefore presents a major selectivity criterion in the inhibition. 45 − 48 Interestingly, the pH dependence of the structure and functional dynamics of HCA II and IX in the absence of any inhibitor has not been probed so far in any of these computer simulation studies.…”

“…Useful information has been extracted from these studies about binding interactions, affinities, and stabilization of the inhibitor-bound enzyme. ,− Simulation studies on the folding and unfolding patterns of HCA IX-c under different conditions have also been reported. , The residues Trp-5, Gln-67, Gln-92, His-94, Glu-106, His-119, Val-131, Thr-200, and Pro-202 have been found to contribute significantly, through π–π, hydrogen bonding, and hydrophobic interactions, in stabilizing the active site of different inhibitor-bound systems. ,− The HCA IX-c binding site is found to be more spacious because it has a smaller hydrophobic group (Val-131) as compared to a larger hydrophobic group (Phe-131) in HCA II. The shape of the ligand therefore presents a major selectivity criterion in the inhibition. − Interestingly, the pH dependence of the structure and functional dynamics of HCA II and IX in the absence of any inhibitor has not been probed so far in any of these computer simulation studies.…”

Pyrazole-sulfonamide scaffold featuring dual-tail strategy as apoptosis inducers in colon cancer. Design, synthesis, biological, and docking studies

“…Pyrazole-Sulfonamide hybrids were reported for their anticancer activities against colon cancer 37 . In an attempt for obtaining new candidates to act against colon cancer, 2-Cyano-N-( 4 introduced methyl and methoxy groups, respectively.…”

“…While designing our target compounds we have been also interested in investigating the use of pyrazolesulfonamide hybrids as they were reported for their anticancer activities against colon cancer 37 . Pyrazole-containing molecules were reported for their potential anticancer activities through acting on various targets 38,39 .…”

Synthesis, characterization, anti-microbial and anti-fungal activity studies of four novel 2-aminopyridine and 2,4-dichloro-5-sulfamoylbenzoic acid salts and their Cu(II) complexes

“…It is known that 2,4-dichloro-5-sulfamoylbenzoic acid derivatives (Hsba) have biological activities such as diuretic (Xia et al 1991, Latosinska et al 2012, antiviral (Latosinska et al 2009), anticonvulsant (Marona and Kiec-Kononowicz 1998), fungicidal, anti-inflammatory (Gaidukevich et al 1984), anti-microbial and anti-fungal (Meena et al 2020, Ilkimen et al 2022) and antiglaucoma (Arslan et al 2002, Yenikaya et al 2010, 2011a, Slawinski et al 2014, Matulis et al 2017, Zakšauskas et al 2022. There are also few reports on the simple transition metal complexes {Na(I) (Latosinska et al 2012), Fe(III) (Ilkimen et al 2020) and Mg(II), Fe(II), Co(II), Ni(II), Cu(II) and Cd(II) (Ilkimen et al 2022)}, proton transfer salts {2aminomethylpyridine (Yenikaya et al 2010), 2-amino-3-methylpyridine and ethylenediamine (Yenikaya et al 2011a)} and mixed ligand metal complexes {2-aminomethylpyridine (Yenikaya et al 2010), 2-amino-3,5-dibromopyridine, 2-amino-3-bromo-5-nitropyridine, 2amino-3-hydroxypyridine, (Ilkimen and Yenikaya 2021), 2-aminomethylpyridine, 4,4'-bipyridine (Liu et al 2014) and 1,3-bis(4-pyridyl)propane (Zhao et al 2015)} of Hsba have been synthesized.…”