Polypharmacology of epacadostat: a potent and selective inhibitor of the tumor associated carbonic anhydrases IX and XII

2019 ◽  
Vol 55 (40) ◽  
pp. 5720-5723 ◽  
Author(s):  
Andrea Angeli ◽  
Marta Ferraroni ◽  
Alessio Nocentini ◽  
Silvia Selleri ◽  
Paola Gratteri ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Selective Inhibitor ◽  
Carbonic Anhydrase Inhibitor ◽  
Carbonic Anhydrases ◽  
Indoleamine 2,3 Dioxygenase

Epacadostat (EPA), a selective indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, has been investigatedin vitroas a human (h) Carbonic Anhydrase Inhibitor (CAI).

Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

2019 ◽  
Vol 25 (39) ◽  
pp. 5266-5278 ◽  
Author(s):  
Katia D'Ambrosio ◽  
Claudiu T. Supuran ◽  
Giuseppina De Simone
Keyword(s):  
Drug Resistance ◽  
Animal Models ◽  
Carbonic Anhydrase ◽  
Drug Target ◽  
Treatment Options ◽  
Parasitic Diseases ◽  
Carbonic Anhydrases ◽  
Extensive Drug Resistance ◽  
Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

scholarly journals Polymorphisms in Brucella Carbonic anhydrase II mediate CO2 dependence and fitness in vivo

2019 ◽  
Author(s):  
JM García-Lobo ◽  
Y Ortiz ◽  
C González-Riancho ◽  
A Seoane ◽  
B Arellano-Reynoso ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Primary Cultures ◽  
Low Frequency ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrases ◽  
Significant Difference ◽  
Dependent Strain

AbstractSome Brucella isolates are known to require an increased concentration of CO2 for growth, especially in the case of primary cultures obtained directly from infected animals. Moreover, the different Brucella species and biovars show a characteristic pattern of CO2 requirement, and this trait has been included among the routine typing tests used for species and biovar differentiation. By comparing the differences in gene content among different CO2-dependent and CO2-independent Brucella strains we have confirmed that carbonic anhydrase II (CA II), is the enzyme responsible for this phenotype in all the Brucella strains tested. Brucella species contain two carbonic anhydrases of the β family, CA I and CA II; genetic polymorphisms exist for both of them in different isolates, but only those putatively affecting the activity of CA II correlate with the CO2 requirement of the corresponding isolate. Analysis of these polymorphisms does not allow the determination of CA I functionality, while the polymorphisms in CA II consist of small deletions that cause a frameshift that changes the C-terminus of the protein, probably affecting its dimerization status, essential for the activity.CO2-independent mutants arise easily in vitro, although with a low frequency ranging from 10−6 to 10−10 depending on the strain. These mutants carry compensatory mutations that produce a full length CA II. At the same time, no change was observed in the sequence coding for CA I. A competitive index assay designed to evaluate the fitness of a CO2-dependent strain compared to its corresponding CO2-independent strain revealed that while there is no significant difference when the bacteria are grown in culture plates, growth in vivo in a mouse model of infection provides a significant advantage to the CO2-dependent strain. This could explain why some Brucella isolates are CO2-dependent in primary isolation. The polymorphism described here also allows the in silico determination of the CO2 requirement status of any Brucella strain.

scholarly journals Azobenzene-based inhibitors of human carbonic anhydrase II

2015 ◽  
Vol 11 ◽  
pp. 1129-1135 ◽  
Author(s):  
Leander Simon Runtsch ◽  
David Michael Barber ◽  
Peter Mayer ◽  
Michael Groll ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Catalytic Activity ◽  
Carbonic Anhydrase ◽  
Drug Class ◽  
Carbonic Anhydrase Ii ◽  
Carbonic Anhydrases ◽  
X Ray ◽  
X Ray Crystallography ◽  
Human Carbonic Anhydrase

Aryl sulfonamides are a widely used drug class for the inhibition of carbonic anhydrases. In the context of our program of photochromic pharmacophores we were interested in the exploration of azobenzene-containing sulfonamides to block the catalytic activity of human carbonic anhydrase II (hCAII). Herein, we report the synthesis and in vitro evaluation of a small library of nine photochromic sulfonamides towards hCAII. All molecules are azobenzene-4-sulfonamides, which are substituted by different functional groups in the 4´-position and were characterized by X-ray crystallography. We aimed to investigate the influence of electron-donating or electron-withdrawing substituents on the inhibitory constant K i. With the aid of an hCAII crystal structure bound to one of the synthesized azobenzenes, we found that the electronic structure does not strongly affect inhibition. Taken together, all compounds are strong blockers of hCAII with K i = 25–65 nM that are potentially photochromic and thus combine studies from chemical synthesis, crystallography and enzyme kinetics.

scholarly journals Coumarin or benzoxazinone bearing benzimidazolium and bis(benzimidazolium) salts; involvement in transfer hydrogenation of acetophenone derivatives and hCA inhibition

2015 ◽  
Vol 4 (5) ◽  
pp. 252-260
Author(s):  
Mert Olgun KarataÅŸ ◽  
Serkan Dayan ◽  
Nilgün Kayacı ◽  
ÇiÄŸdem Bilen ◽  
Emre Yavuz ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Bond Activation ◽  
Suzuki Reaction ◽  
Catalytic Reactions ◽  
Transfer Hydrogenation ◽  
Carbonic Anhydrases ◽  
Acetophenone Derivatives ◽  
Coumarin Compounds ◽  
Benzimidazolium Salts

Four new salts of benzimidazolium and bis(benzimidazolium) which include coumarin or benzoxazinone moieties were synthesized and the structures of the newly synthesized compounds were elucidated on the basis of spectral analyses such as 1H-NMR, 13C-NMR, HSQC, IR, LC-MS and elemental analysis. Benzimidazolium salts were used intensively as N-heterocyclic carbene (NHC) precursors in the various catalytic reactions such as transfer hydrogenation (TH), C-H bond activation, Heck, Suzuki reaction etc. With the prospect of potential NHC precursor properties of the synthesized compounds, they were employed in the (TH) reaction of p-substitute acetophenones (acetophenone, p-methyl acetophenone, p-chloro acetophenone) and good yields were observed. Coumarin compounds are known as inhibitor of carbonic anhydrase and inhibition effects of the synthesized compounds on human carbonic anhydrases (hCA) were investigated as in vitro. The in vitro results demonstrated that all compounds inhibited hCA I and hCA II activity. Among the synthesized compounds 1,4-bis(1-((6,8-dimethyl-2H-chromen-2-one-4-yl)methyl)benzimidazolium-3-yl)butane dichloride was found to be the most active IC50= 5.55 mM and 6.06 mM for hCA I and hCA II, respectively.

CHLOROTHIAZIDE

PEDIATRICS ◽  
1958 ◽  
Vol 22 (2) ◽  
pp. 236-237
Author(s):  
JOHN D. CRAWFORD
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Carbonic Anhydrase ◽  
Renal Insufficiency ◽  
Chronic Renal Insufficiency ◽  
Free Water ◽  
Carbonic Anhydrase Inhibitor ◽  
Diuretic Agent

CHLOROTHIAZIDE is a new, orally effective diuretic agent chemically related to acetazolamide. Curiously, it is a considerably less potent carbonic anhydrase inhibitor, at least in vitro and, in vivo, its effect has been found additive to that of acetazolamide as it is to the action of the mercurials. Laragh's observations suggest that chlorothiazide inhibits the process of solute reabsorption which normally gives rise to "free" water in the urine. Thus, it may well have a locus of action in the kidney different from that of its chemical cousin or the mercury derivities. There have been optimistic reports of its efficacy in a variety of edema states including nephrosis, cirrhosis of the liver, congestive heart failure, acute hemorrhagic nephritis and chronic renal insufficiency.

Carbonic Anhydrase Inhibitory Potential of 1,2,4-triazole-3-thione Derivatives of Flurbiprofen, Ibuprofen and 4-tert-butylbenzoic Hydrazide: Design, Synthesis, Characterization, Biochemical Evaluation, Molecular Docking and Dynamic Simulation Studies

2019 ◽  
Vol 15 (3) ◽  
pp. 298-310
Author(s):  
Saghir Abbas ◽  
Sumera Zaib ◽  
Shafiq Ur Rahman ◽  
Saqib Ali ◽  
Shahid Hameed ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Carbonic Anhydrase ◽  
13C Nmr Spectroscopy ◽  
Breast Adenocarcinoma ◽  
Synthetic Approach ◽  
Carbonic Anhydrases ◽  
Dynamic Simulations ◽  
Vitro Assay ◽  
Inhibitory Potential

Background:The over-expression of the carbonic anhydrases results in some specific carcinomas including pancreatic, gastric and brain tumor. Tumors are distinguished under hypoxic conditions and various investigations are being carried out to target the known hypoxic areas of the tumors to increase the sensitivity towards standard therapeutic treatment.Objective:Herein, we have designed and synthesized some biologically important esters, hydrazides, thiocarbamates, 1,2,4-triazole-3-thiones and Schiff bases. The purpose of the research was to evaluate the derivative against carbonic anhydrase and to assess the toxicity of the same compounds.Method:The structures of all the compounds were characterized by FT-IR, mass spectrometry, elemental analysis, 1H and 13C NMR spectroscopy. The synthetic derivatives were screened for their inhibitory potential against carbonic anhydrase II by in vitro assay. Double reciprocal plots for inhibition kinetics of the potent compounds were constructed and mode of inhibition was determined. Furthermore, to check the cytotoxicity, these derivatives were tested against human breast adenocarcinoma by MTT method.Results:X-ray diffraction analysis of the compounds 10, 14 and 15 showed that they did not have any π-π or C-H…&π interactions. The experimental results were validated by molecular docking and dynamic simulations of the potent compounds in the active pocket of enzyme. Important binding interactions of potent compounds with the key residues in the active site of the carbonic anhydrase enzyme were revealed. Drug likeness profile of the derivatives was evaluated to determine the physicochemical properties.Conclusion:The proposed synthetic approach provides a suitable platform for the generation of a new library of compounds which could potentially be employed in the future testing and optimization of inhibitor potencies.

scholarly journals Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro

2000 ◽  
Vol 97 (5) ◽  
pp. 2220-2224 ◽  
Author(s):  
S. Parkkila ◽  
H. Rajaniemi ◽  
A.-K. Parkkila ◽  
J. Kivela ◽  
A. Waheed ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Cancer Cells ◽  
Renal Cancer ◽  
Carbonic Anhydrase Inhibitor

Computational Studies on Isolated Compounds of Sclerochloa dura; their Efficacy towards Carbonic Anhydrase Inhibition and Anti-cancer Drug Targets

2021 ◽  
Vol 18 ◽  
Author(s):  
Majid Ali ◽  
Asma Zaidi ◽  
Umar Farooq ◽  
Rizwana Sarwar ◽  
Syed Majid Bukhari
Keyword(s):  
Carbonic Anhydrase ◽  
Binding Affinity ◽  
Anticancer Drug ◽  
Active Site ◽  
Drug Targets ◽  
Docking Studies ◽  
Cancer Drug ◽  
Hydroxyl Groups ◽  
Carbonic Anhydrases

Background: In the previous study, we reported the isolation of six compounds from Sclerochloa dura and their in-vitro anti-inflammatory potential by their ability to inhibit phospholipase A2 (PLA2). The objective of the current study is to inspect the effect of these compounds on other expected targets. Methods: For this purpose, various targets and percentage activities are predicted through CoFFer (QSAR) web service. All six compounds under investigation represented 99-100% activity towards carbonic anhydrases (CAs) and 90-100% activity towards anticancer drug targets. As the active site of most of the carbonic anhydrase isozymes is conserved, we selected cytosolic human carbonic anhydrase II (hCA II) for docking studies which is ubiquitous and involved in various human disorders such as glaucoma, pulmonary edema, and epilepsy. Anticancer drug targets include vascular endothelial growth factor receptor 2 (VEGFR2), glucocorticoid receptor (GR), and tyrosine-protein kinase (c-SRC). Interaction of these compounds with hCA II (PDB ID: 3P4V) and anticancer drug targets such as VEGFR2 (ID: 3WZD), GR (ID: 5G5W), and c-SRC (ID: 2SRC) was analyzed through molecular docking studies using MOE (Molecular Operating Environment). Results: The findings suggested that most of these compounds represent excellent binding affinity with hCA II by interacting with zinc-coordinated water molecules through sulfonic acid and hydroxyl groups present in the blends. Similarly, five out of six compounds represented excellent interaction with VEGFR2. Interactions with GR indicated that compounds 2, 3, and 6 binds effectively compared to their co-crystallized ligands. However, among these, the excellent binding affinity with c-SRC was demonstrated by compounds 3 and 6. Conclusion: This study revealed that all these compounds exhibited excellent interaction with the active site of hCA II, however in the light of previously reported data and due to membrane barrier, only compound 1 (due to long hydrophobic tail) and compound 4 (due to absence of bulky carbohydrate groups), can only penetrate inside the cytosol. Compounds 2, 3, 4, and 6 containing bulky carbohydrate moieties cannot penetrate inside the cell, therefore, they might have selective nature towards membrane-bounded tumor-associated hCA IX. This anti-tumor property of compounds was also proved by docking studies with VEGFR2, GR, and c-SRC. Therefore, these compounds may have a synergistic effect against inflammation and cancer. The ADMET studies show that compounds have moderate absorption and permeability along with slight toxicity.

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