Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX.

Download Full-text

Extending the Inhibition Profiles of Coumarin-Based Compounds Against Human Carbonic Anhydrases: Synthesis, Biological, and In Silico Evaluation

Molecules ◽

10.3390/molecules24193580 ◽

2019 ◽

Vol 24 (19) ◽

pp. 3580 ◽

Cited By ~ 2

Author(s):

Kartsev ◽

Geronikaki ◽

Bua ◽

Nocentini ◽

Petrou ◽

...

Keyword(s):

Active Site ◽

Inhibitory Activity ◽

Binding Mode ◽

Carbonic Anhydrases ◽

Reference Drug ◽

Physiological Conditions ◽

Computational Procedures ◽

Living Organisms ◽

Human Isoforms ◽

Potent Inhibitory Activity

Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the fundamental reaction of CO2 hydration in all living organisms and are actively involved in the regulation of a plethora of pathological and physiological conditions. A set of new coumarin/ dihydrocoumarin derivatives was here synthesized, characterized, and tested as human CA inhibitors. Their inhibitory activity was evaluated against the cytosolic human isoforms hCA I and II and the transmembrane hCA IX and hCA XII. Two compounds showed potent inhibitory activity against hCA IX, being more active or equipotent with the reference drug acetazolamide. Computational procedures were used to investigate the binding mode of this class of compounds within the active site of hCA IX and XII that are validated as anti-tumor targets.

Download Full-text

Aryl-4,5-dihydro-1H-pyrazole-1-carboxamide Derivatives Bearing a Sulfonamide Moiety Show Single-digit Nanomolar-to-Subnanomolar Inhibition Constants against the Tumor-associated Human Carbonic Anhydrases IX and XII

International Journal of Molecular Sciences ◽

10.3390/ijms21072621 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2621

Author(s):

Priya Hargunani ◽

Nikhil Tadge ◽

Mariangela Ceruso ◽

Janis Leitans ◽

Andris Kazaks ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Inhibitory Activity ◽

Phenyl Ring ◽

Drug Targets ◽

Binding Mode ◽

Docking Studies ◽

Carbonic Anhydrases ◽

Single Digit ◽

Ca Ix ◽

Shed Light

A series of new 3-phenyl-5-aryl-N-(4-sulfamoylphenyl)-4,5-dihydro-1H-pyrazole-1-carboxamide derivatives was designed here, synthesized, and studied for carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory activity against the human (h) isozymes I, II, and VII (cytosolic, off-target isoforms), and IX and XII (anticancer drug targets). Generally, CA I was not effectively inhibited, whereas effective inhibitors were identified against both CAs II (KIs in the range of 5.2–233 nM) and VII (KIs in the range of 2.3–350 nM). Nonetheless, CAs IX and XII were the most susceptible isoforms to this class of inhibitors. In particular, compounds bearing an unsubstituted phenyl ring at the pyrazoline 3 position showed 1.3–1.5 nM KIs against CA IX. In contrast, a subset of derivatives having a 4-halo-phenyl at the same position of the aromatic scaffold even reached subnanomolar KIs against CA XII (0.62–0.99 nM). Docking studies with CA IX and XII were used to shed light on the derivative binding mode driving the preferential inhibition of the tumor-associated CAs. The identified potent and selective CA IX/XII inhibitors are of interest as leads for the development of new anticancer strategies.

Download Full-text

The Effect of Nanoparticles on the Structure and Enzymatic Activity of Human Carbonic Anhydrase I and II

Molecules ◽

10.3390/molecules25194405 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4405

Author(s):

Celia Cabaleiro-Lago ◽

Martin Lundqvist

Keyword(s):

Carbonic Anhydrase ◽

Conformational Changes ◽

Catalytic Efficiency ◽

The Body ◽

Carbonic Anhydrases ◽

Nanoparticle Surface ◽

Mountain Sickness ◽

Obesity And Cancer ◽

Final Effect ◽

Human Isoforms

Human carbonic anhydrases (hCAs) belong to a well characterized group of metalloenzymes that catalyze the conversion of carbonic dioxide into bicarbonate. There are currently 15 known human isoforms of carbonic anhydrase with different functions and distribution in the body. This links to the relevance of hCA variants to several diseases such as glaucoma, epilepsy, mountain sickness, ulcers, osteoporosis, obesity and cancer. This review will focus on two of the human isoforms, hCA I and hCA II. Both are cytosolic enzymes with similar topology and 60% sequence homology but different catalytic efficiency and stability. Proteins in general adsorb on surfaces and this is also the case for hCA I and hCA II. The adsorption process can lead to alteration of the original function of the protein. However, if the function is preserved interesting biotechnological applications can be developed. This review will cover the knowledge about the interaction between hCAs and nanomaterials. We will highlight how the interaction may lead to conformational changes that render the enzyme inactive. Moreover, the importance of different factors on the final effect on hCAs, such as protein stability, protein hydrophobic or charged patches and chemistry of the nanoparticle surface will be discussed.

Download Full-text

ChemInform Abstract: An Inhibitor-Like Binding Mode of a Carbonic Anhydrase Activator within the Active Site of Isoform II.

ChemInform ◽

10.1002/chin.201210155 ◽

2012 ◽

Vol 43 (10) ◽

pp. no-no

Author(s):

Khyati Dave ◽

Marc A. Ilies ◽

Andrea Scozzafava ◽

Claudia Temperini ◽

Daniela Vullo ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Active Site ◽

Binding Mode

Download Full-text

Benzylaminoethyureido-Tailed Benzenesulfonamides: Design, Synthesis, Kinetic and X-ray Investigations on Human Carbonic Anhydrases

International Journal of Molecular Sciences ◽

10.3390/ijms21072560 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2560 ◽

Cited By ~ 2

Author(s):

Majid Ali ◽

Murat Bozdag ◽

Umar Farooq ◽

Andrea Angeli ◽

Fabrizio Carta ◽

...

Keyword(s):

Carbonic Anhydrase ◽

Design Strategy ◽

Binding Mode ◽

Crystallographic Analysis ◽

Carbonic Anhydrases ◽

Detailed Structure ◽

Design Synthesis ◽

X Ray ◽

Structure Activity ◽

New Compounds

A drug design strategy of carbonic anhydrase inhibitors (CAIs) belonging to sulfonamides incorporating ureidoethylaminobenzyl tails is presented. A variety of substitution patterns on the ring and the tails, located on para- or meta- positions with respect to the sulfonamide warheads were incorporated in the new compounds. Inhibition of human carbonic anhydrases (hCA) isoforms I, II, IX and XII, involving various pathologies, was assessed with the new compounds. Selective inhibitory profile towards hCA II was observed, the most active compounds being low nM inhibitors (KIs of 2.8–9.2 nM, respectively). Extensive X-ray crystallographic analysis of several sulfonamides in an adduct with hCA I allowed an in-depth understanding of their binding mode and to lay a detailed structure-activity relationship.

Download Full-text

Activation Effects of Carnosine- and Histidine-Containing Dipeptides on Human Carbonic Anhydrases: A Comprehensive Study

International Journal of Molecular Sciences ◽

10.3390/ijms21051761 ◽

2020 ◽

Vol 21 (5) ◽

pp. 1761 ◽

Cited By ~ 3

Author(s):

Giulio Vistoli ◽

Giancarlo Aldini ◽

Laura Fumagalli ◽

Clelia Dallanoce ◽

Andrea Angeli ◽

...

Keyword(s):

Computational Study ◽

Complex Structure ◽

Imidazole Ring ◽

Binding Mode ◽

Carbonic Anhydrases ◽

Enzyme Active Site ◽

Structure Activity ◽

Human Isoforms ◽

Micromolar Range ◽

Comprehensive Study

l-Carnosine (β-Ala-l-His) and several other histidine-containing peptides, including two N-methylated forms on the imidazole ring (l-anserine and l-balenine), two derivatives modified on the carboxyl function (carcinine and l-carnosinamide), two analogues differing in the length of the N-terminal residue (l-homocarnosine and Gly-l-His) and the N-acetyl derivatives, were investigated as activators of four isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). The four human isoforms hCA I, II, VA and IX were activated in the low to high micromolar range, with a rather complex structure activity relationship. A performed computational study allowed us to rationalize these results and to propose a binding mode of these activators within the enzyme active site. Similarly to other CA activators, the here studied peptides could find relevant pharmacological applications such as in the management of CA deficiencies, for therapy memory and enhancing cognition or for artificial tissues engineering.

Download Full-text

A Closer Look at the Active Site of γ-Class Carbonic Anhydrases: High-Resolution Crystallographic Studies of the Carbonic Anhydrase fromMethanosarcina thermophila†,‡

Biochemistry ◽

10.1021/bi000204s ◽

2000 ◽

Vol 39 (31) ◽

pp. 9222-9231 ◽

Cited By ~ 111

Author(s):

Tina M. Iverson ◽

Birgit E. Alber ◽

Caroline Kisker ◽

James G. Ferry ◽

Douglas C. Rees

Keyword(s):

High Resolution ◽

Carbonic Anhydrase ◽

Active Site ◽

Carbonic Anhydrases

Download Full-text

Discovery of novel isatin-based sulfonamides with potent and selective inhibition of the tumor-associated carbonic anhydrase isoforms IX and XII

Organic & Biomolecular Chemistry ◽

10.1039/c5ob00688k ◽

2015 ◽

Vol 13 (23) ◽

pp. 6493-6499 ◽

Cited By ~ 35

Author(s):

Özlen Güzel-Akdemir ◽

Atilla Akdemir ◽

Nilgün Karalı ◽

Claudiu T. Supuran

Keyword(s):

Carbonic Anhydrase ◽

Inhibitory Activity ◽

Selective Inhibition ◽

Carbonic Anhydrases

A series of 2/3/4-[(2-oxo-1,2-dihydro-3H-indol-3-ylidene)amino]benzenesulfonamides, obtained from substituted isatins and 2-, 3- or 4-aminobenzenesulfonamide, showed low nanomolar inhibitory activity against the tumor associated carbonic anhydrases IX and XII.

Download Full-text