Inhibition of carbonic anhydrases by a substrate analog: benzyl carbamate directly coordinates the catalytic zinc ion mimicking bicarbonate binding

2018 ◽  
Vol 54 (73) ◽  
pp. 10312-10315 ◽  
Author(s):  
Giuseppina De Simone ◽  
Andrea Angeli ◽  
Murat Bozdag ◽  
Claudiu T. Supuran ◽  
Jean-Yves Winum ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Mode ◽  
Zinc Ion ◽  
Carbonic Anhydrases ◽  
Carbonic Anhydrase Inhibitors ◽  
Lead Compounds ◽  
Substrate Analog ◽  
Catalytic Zinc

N-Unsubstituted carbamates can be used as lead compounds for the development of carbonic anhydrase inhibitors possessing a binding mode similar to bicarbonate.

scholarly journals Synthesis and Evaluation of New Phthalazine Urea and Thiourea Derivatives as Carbonic Anhydrase Inhibitors

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Nurcan Berber ◽  
Mustafa Arslan ◽  
Emre Yavuz ◽  
Cigdem Bilen ◽  
Nahit Gencer
Keyword(s):  
Carbonic Anhydrase ◽  
Nitro Group ◽  
Zinc Ion ◽  
Inhibitory Effect ◽  
Carbonic Anhydrases ◽  
Coumarin Derivatives ◽  
Inhibitory Effects ◽  
Carbonic Anhydrase Inhibitors ◽  
Thiourea Derivatives ◽  
Amine Derivative

A new series of phthalazine substituted urea and thiourea derivatives were synthesized, and their inhibitory effects on the activity of purified human carbonic anhydrases (hCAs I and II) were evaluated. 2H-Indazolo[2,1-b]phthalazine-trione derivative(1)was prepared with 4-nitrobenzaldehyde, dimedone, and phthalhydrazide in the presence of TFA in DMF, and nitro group was reduced to amine derivative(2)with SnCl2·2H2O. The compound was reacted with isocyanates and isothiocyanates to get the final products(3a–p). The results showed that all the synthesized compounds inhibited the CA isoenzymes activity.3a(IC50= 6.40 µM for hCA I and 6.13 µM for hCA II) has the most inhibitory effect. The synthesized compounds are very bulky to be able to bind near the zinc ion, and they much more probably bind as the coumarin derivatives.

scholarly journals 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

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.

scholarly journals Carborane-Based Carbonic Anhydrase Inhibitors: Insight into CAII/CAIX Specificity from a High-Resolution Crystal Structure, Modeling, and Quantum Chemical Calculations

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Pavel Mader ◽  
Adam Pecina ◽  
Petr Cígler ◽  
Martin Lepšík ◽  
Václav Šícha ◽  
...  
Keyword(s):  
Crystal Structure ◽  
High Resolution ◽  
Carbonic Anhydrase ◽  
Quantum Chemical Calculations ◽  
Quantum Chemical ◽  
Computational Analysis ◽  
Structure Modeling ◽  
Carbonic Anhydrases ◽  
Carbonic Anhydrase Inhibitors ◽  
Insight Into

Carborane-based compounds are promising lead structures for development of inhibitors of carbonic anhydrases (CAs). Here, we report structural and computational analysis applicable to structure-based design of carborane compounds with selectivity toward the cancer-specific CAIX isoenzyme. We determined the crystal structure of CAII in complex with 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane at 1.0 Å resolution and used this structure to model the 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane interactions with CAIX. A virtual glycine scan revealed the contributions of individual residues to the energy of binding of 1-methylenesulfamide-1,2-dicarba-closo-dodecaborane to CAII and CAIX, respectively.

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

2020 ◽  
Vol 21 (7) ◽  
pp. 2560 ◽  
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.

scholarly journals Structural and Functional Analysis of the Complex between Citrate and the Zinc Peptidase Carboxypeptidase A

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Daniel Fernández ◽  
Ester Boix ◽  
Irantzu Pallarès ◽  
Francesc X. Avilés ◽  
Josep Vendrell
Keyword(s):  
Oral Delivery ◽  
Binding Mode ◽  
Competitive Inhibitor ◽  
Zinc Ion ◽  
X Ray Diffraction ◽  
Carboxypeptidase A ◽  
X Ray ◽  
Citrate Complex ◽  
First Time ◽  
Catalytic Zinc

A high-resolution carboxypeptidase-Zn2+-citrate complex was studied by X-ray diffraction and enzyme kinetics for the first time. The citrate molecule acts as a competitive inhibitor of this benchmark zinc-dependent peptidase, chelating the catalytic zinc ion in the active site of the enzyme and inducing a conformational change such that carboxypeptidase adopts the conformation expected to occur by substrate binding. Citrate adopts an extended conformation with half of the molecule facing the zinc ion, while the other half is docked in the S1′ hydrophobic specificity pocket of the enzyme, in contrast with the binding mode expected for a substrate like phenylalanine or a peptidomimetic inhibitor like benzylsuccinic acid. Combined structural and enzymatic analysis describes the characteristics of the binding of this ligand that, acting against physiologically relevant zinc-dependent proteases, may serve as a general model in the design of new drug-protecting molecules for the oral delivery of drugs of peptide origin.

scholarly journals Amino Acids as Building Blocks for Carbonic Anhydrase Inhibitors

2018 ◽  
Author(s):  
Niccolò Chiaramonte ◽  
Maria Novella Romanelli ◽  
Elisabetta Teodori ◽  
Claudiu Supuran
Keyword(s):  
Organic Chemistry ◽  
Amino Acids ◽  
Carbonic Anhydrase ◽  
Chemical Properties ◽  
Building Blocks ◽  
Carbonic Anhydrases ◽  
Carbonic Anhydrase Inhibitors ◽  
Physiological Processes ◽  
Long Time ◽  
Reversible Hydration

Carbonic Anhydrases (CAs) are a superfamily of metalloenzymes widespread in all life kingdoms, classified into seven genetically different families (α-θ). These enzymes catalyse the reversible hydration of carbonic anhydride (CO2), generating bicarbonate (HCO3-) and protons (H+). Fifteen isoforms of human CA (hCA I-XV) have been isolated, their presence being fundamental for the regulation of many physiological processes. In addition, overexpression of some isoforms has been associated with the outbreak or the progression of several diseases. For this reason, for a long time CA inhibitors (CAIs) are used in the control of glaucoma and as diuretics. Furthermore, the search for new potential CAIs for other pharmacological applications is a very active field. Amino acids constitute the smallest fundamental monomers of protein and, due to their useful bivalent chemical properties, are widely used in organic chemistry. Both proteinogenic and non-proteinogenic amino acids have been extensively used to synthesize CAIs. This article provides an overview of the different strategies that have been used to design new CAIs containing amino acids, and how these bivalent molecules influence the properties of the inhibitors.

scholarly journals Non-classical β-carbonic anhydrase inhibitors-towards novel anti-mycobacterials

MedChemComm ◽  
2014 ◽  
Vol 5 (10) ◽  
pp. 1563-1566 ◽  
Author(s):  
Natascha von Gnielinski ◽  
Lisa Nienaber ◽  
Lyndel Mason ◽  
Samantha Ellis ◽  
James A. Triccas ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Drug Targets ◽  
Carbonic Anhydrases ◽  
Carbonic Anhydrase Inhibitors ◽  
Essential Protein

Mycobacterial carbonic anhydrases, such as the essential protein Rv3588c, are attractive drug targets since they constitute a different class of carbonic anhydrases than those found in humans.

scholarly journals 2-Mercaptobenzoxazoles: a class of carbonic anhydrase inhibitors with a novel binding mode to the enzyme active site

2020 ◽  
Vol 56 (59) ◽  
pp. 8297-8300
Author(s):  
Murat Bozdag ◽  
Claudiu T. Supuran ◽  
Davide Esposito ◽  
Andrea Angeli ◽  
Fabrizio Carta ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Active Site ◽  
Binding Mode ◽  
Lead Compound ◽  
Carbonic Anhydrase Inhibitors ◽  
Enzyme Active Site

2-Mercaptobenzoxazole represents an interesting lead compound alternative to the classical sulfonamides for the development of selective carbonic anhydrase inhibitors.

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