962 results on '"Carbonic Anhydrase I"'
Search Results
2. M1-Type Macrophages Secrete TNF-α to Stimulate Vascular Calcification by Upregulating CA1 and CA2 Expression in VSMCs
- Author
-
Song X, Song Y, Ma Q, Fang K, and Chang X
- Subjects
atherosclerosis ,calcification ,carbonic anhydrase i ,carbonic anhydrase ii ,macrophages ,tnf- ,Pathology ,RB1-214 ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Xianqin Song,1 Yu Song,1 Quanping Ma,2 Kehua Fang,3 Xiaotian Chang1 1Medical Research Center of the Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of China; 2Clinical Laboratory, The fourth People’s Hospital of Jinan, Jinan, Shandong, People’s Republic of China; 3Clinical Laboratory of the Affiliated Hospital of Qingdao University, Qingdao, Shandong, People’s Republic of ChinaCorrespondence: Xiaotian Chang, Medical Research Center of the Affiliated Hospital of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China, Tel/Fax +86 0532-82917331, Email changxt@126.comPurpose: Vascular calcification is a hallmark of atherosclerosis (AS). We and others confirmed that carbonic anhydrase I (CA1) and CA2 increased expression and catalyzed calcium deposition in atherosclerotic aortas. Macrophages have been demonstrated to be strongly related to AS. This study aimed to clarify how and which macrophage subtypes regulate CA1 and CA2 expression to stimulate aortic calcification.Methods and Results: THP-1 cells were induced to form M0, M1 and M2 macrophage subtypes. These cells and their culture supernatants were separately incubated with human vascular smooth muscle cells (VSMCs). Calcification was strongly increased in VSMCs treated with β-GP, a chemical inducer of cellular calcification, following incubation with M1 macrophages or their culture supernatants, and was much higher than that in VSMCs treated with β-GP alone. Meanwhile, the expression of CA1 and CA2, as well as calcification marker genes, including Runx2, BMP-2 and ALP, was increased in VSMCs during this process. TNF-α levels were also increased in the culture medium of M1 macrophages. M0 and M2 macrophages or their supernatants did not significantly stimulate calcification in VSMCs. Following transfection with anti-CA1 or CA2 siRNAs, β-GP-induced VSMCs showed decreased calcification, but the calcification level was partially increased when those VSMCs were incubated with the supernatants of M1 macrophages, while CA1 and CA2 expression as well as TNF-α levels were also elevated. When VSMCs were treated with TNF-α without β-GP induction, calcification and the expression of CA1 and CA2 were also significantly increased.Conclusion: The results of this study suggest that M1 macrophages can increase CA1 and CA2 expression to promote atherosclerotic calcification in VSMCs by secreting TNF-α.Keywords: atherosclerosis, calcification, carbonic anhydrase I, carbonic anhydrase II, macrophages, TNF-α
- Published
- 2023
3. Computational Evaluation of the Potential of Salicylate Compound from Syzygium aromaticum on Carbonic Anhydrase I as a Gastric Acid Stimulant.
- Author
-
Zainul, Rahadian, Verawati, Rismi, Rita, Rauza Sukma, Ranuharja, Fadhli, Ghufron, Musa, Samala, Agariadne Dwinggo, Satriawan, Herland, Ghifari, Muhammad Raffi, Purnamasari, Devi, Mandeli, Riso Sari, Lubis, Amalia Putri, Kharisma, Viol Dhea, Jakhmola, Vikash, Rebezov, Maksim, and Ansori, ANM
- Subjects
- *
CARBONIC anhydrase , *GASTRIC acid , *CLOVE tree , *SALICYLATES , *STIMULANTS , *PROTEIN structure , *H2 receptor antagonists , *BENZENESULFONAMIDES - Abstract
This article explores the potential of the salicylate compound (Syzygium Aromaticum) as a stimulant for Carbonic Anhydrase I in gastric acid secretion, using a computational approach. The research methods include molecular modeling with Pymol and Pyrex, determination of compound structure and interactions with Protein Plus, and examination of physicochemical properties using the Lipinski Rule. The results show that the Binding Affinity of salicylate with Carbonic Anhydrase I ranges from -7.3 to -6.5, with RMSD values of 0, 2.102, and 2.212, indicating good modeling quality. The interaction between salicylate and Carbonic Anhydrase I is also supported by the findings from Protein Plus. Furthermore, the salicylate compound complies with the Lipinski Rule, with a molecular weight of 137, 1 hydrogen bond donor, 3 hydrogen bond acceptors, a log P value of 0.34, and a molar reactivity of 34.16. This study highlights the prospect of salicylate as a potential modulator of Carbonic Anhydrase I. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
4. Effect of Fetuin-A and oxidative stress on the occurrence of unexplained infertility.
- Author
-
Taşkan, Tuba, Turan, Taylan, Duvan, Zehra Candan İltemir, and Gönenç, Aymelek
- Subjects
ALPHA fetoproteins ,OXIDATIVE stress ,INFERTILITY ,HEALTH outcome assessment ,ENZYME-linked immunosorbent assay - Abstract
Copyright of Turkish Journal of Obstetrics & Gynecology is the property of Galenos Yayinevi Tic. LTD. STI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
- Published
- 2023
- Full Text
- View/download PDF
5. Role of Non-Covalent Interactions in Carbonic Anhydrase I—Topiramate Complex Based on QM/MM Approach.
- Author
-
Wojtkowiak, Kamil and Jezierska, Aneta
- Subjects
- *
CARBONIC anhydrase , *ATOMS in molecules theory , *LIGAND binding (Biochemistry) , *NATURAL orbitals , *TOPIRAMATE - Abstract
Carbonic anhydrase (CA) I with a Topiramate (TPM) complex was investigated on the basis of a Quantum Mechanics/Molecular Mechanics (QM/MM) approach. The QM part was treated using Density Functional Theory (DFT) while the MM was simulated using Amberff14SB and GAFF force fields. In addition, the TIP3P model was applied to reproduce the polar environment influence on the studied complex. Next, three snapshots (after 5 ps, 10 ps, and 15 ps of the simulation time) were taken from the obtained trajectory to provide an insight into the non-covalent interactions present between the ligand and binding pocket of the protein. Our special attention was devoted to the binding site rearrangement, which is known in the literature concerning the complex. This part of the computations was performed using ω B97X functional with Grimme D3 dispersion corrections as well as a Becke–Johnson damping function (D3-BJ). Two basis sets were applied: def2-SVP (for larger models) and def2-TZVPD (for smaller models), respectively. In order to detect and describe non-covalent interactions between amino acids of the binding pocket and the ligand, Independent Gradient Model based on Hirshfeld partitioning (IGMH), Interaction Region Indicator (IRI), Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbitals (NBO) methods were employed. Finally, Symmetry-Adapted Perturbation Theory (SAPT) was applied for energy decomposition between the ligand and protein. It was found that during the simulation time, the ligand position in the binding site was preserved. Nonetheless, amino acids interacting with TPM were exchanging during the simulation, thus showing the binding site reorganization. The energy partitioning revealed that dispersion and electrostatics are decisive factors that are responsible for the complex stability. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. Structural Characterization of Native Proteins and Protein Complexes by Electron Ionization Dissociation-Mass Spectrometry
- Author
-
Li, Huilin, Sheng, Yuewei, McGee, William, Cammarata, Michael, Holden, Dustin, and Loo, Joseph A
- Subjects
Clinical Research ,Carbonic Anhydrase I ,Dimerization ,Humans ,Ligands ,Photolysis ,Point Mutation ,Protein Unfolding ,Spectrometry ,Mass ,Electrospray Ionization ,Spectroscopy ,Fourier Transform Infrared ,Superoxide Dismutase-1 ,Ultraviolet Rays ,Analytical Chemistry ,Other Chemical Sciences - Abstract
Mass spectrometry (MS) has played an increasingly important role in the identification and structural and functional characterization of proteins. In particular, the use of tandem mass spectrometry has afforded one of the most versatile methods to acquire structural information for proteins and protein complexes. The unique nature of electron capture dissociation (ECD) for cleaving protein backbone bonds while preserving noncovalent interactions has made it especially suitable for the study of native protein structures. However, the intra- and intermolecular interactions stabilized by hydrogen bonds and salt bridges can hinder the separation of fragments even with preactivation, which has become particularly problematic for the study of large macromolecular proteins and protein complexes. Here, we describe the capabilities of another activation method, 30 eV electron ionization dissociation (EID), for the top-down MS characterization of native protein-ligand and protein-protein complexes. Rich structural information that cannot be delivered by ECD can be generated by EID. EID allowed for the comparison of the gas-phase and the solution-phase structural stability and unfolding process of human carbonic anhydrase I (HCA-I). In addition, the EID fragmentation patterns reflect the structural similarities and differences among apo-, Zn-, and Cu,Zn-superoxide dismutase (SOD1) dimers. In particular, the structural changes due to Cu-binding and a point mutation (G41D) were revealed by EID-MS. The performance of EID was also compared to that of 193 nm ultraviolet photodissociation (UVPD), which allowed us to explore their qualitative similarities and differences as potential valuable tools for the MS study of native proteins and protein complexes.
- Published
- 2017
7. Role of Non-Covalent Interactions in Carbonic Anhydrase I—Topiramate Complex Based on QM/MM Approach
- Author
-
Kamil Wojtkowiak and Aneta Jezierska
- Subjects
Carbonic anhydrase I ,Topiramate (TPM) ,non-covalent interactions ,QM/MM ,DFT ,IGMH ,Medicine ,Pharmacy and materia medica ,RS1-441 - Abstract
Carbonic anhydrase (CA) I with a Topiramate (TPM) complex was investigated on the basis of a Quantum Mechanics/Molecular Mechanics (QM/MM) approach. The QM part was treated using Density Functional Theory (DFT) while the MM was simulated using Amberff14SB and GAFF force fields. In addition, the TIP3P model was applied to reproduce the polar environment influence on the studied complex. Next, three snapshots (after 5 ps, 10 ps, and 15 ps of the simulation time) were taken from the obtained trajectory to provide an insight into the non-covalent interactions present between the ligand and binding pocket of the protein. Our special attention was devoted to the binding site rearrangement, which is known in the literature concerning the complex. This part of the computations was performed using ωB97X functional with Grimme D3 dispersion corrections as well as a Becke–Johnson damping function (D3-BJ). Two basis sets were applied: def2-SVP (for larger models) and def2-TZVPD (for smaller models), respectively. In order to detect and describe non-covalent interactions between amino acids of the binding pocket and the ligand, Independent Gradient Model based on Hirshfeld partitioning (IGMH), Interaction Region Indicator (IRI), Quantum Theory of Atoms in Molecules (QTAIM) and Natural Bond Orbitals (NBO) methods were employed. Finally, Symmetry-Adapted Perturbation Theory (SAPT) was applied for energy decomposition between the ligand and protein. It was found that during the simulation time, the ligand position in the binding site was preserved. Nonetheless, amino acids interacting with TPM were exchanging during the simulation, thus showing the binding site reorganization. The energy partitioning revealed that dispersion and electrostatics are decisive factors that are responsible for the complex stability.
- Published
- 2023
- Full Text
- View/download PDF
8. Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide-hydantoin hybrids.
- Author
-
Abdoli M, Bonardi A, Gratteri P, Supuran CT, and Žalubovskis R
- Subjects
- Humans, Carbonic Anhydrase IX, Structure-Activity Relationship, Carbonic Anhydrase I, Carbonic Anhydrase II, Protein Isoforms metabolism, Phthalimides pharmacology, Carbonic Anhydrase Inhibitors chemistry, Molecular Structure, Carbonic Anhydrases metabolism, Hydantoins pharmacology
- Abstract
A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms hCA I, hCA II, and hCA VII, secreted isoform hCA VI, and the transmembrane hCA IX, by a stopped-flow CO
2 hydrase assay. Although all newly developed compounds were totally inactive on hCA I and mainly ineffective towards hCA II, they generally exhibited moderate repressing effects on hCA VI, VII, and IX with KI s values in the submicromolar to micromolar ranges. The salts 3a and 3b , followed by derivative 5 , displayed the best inhibitory activity of all the evaluated compounds and their binding mode was proposed in silico . These compounds can also be considered interesting starting points for the development of novel pharmacophores for this class of enzyme inhibitors.- Published
- 2024
- Full Text
- View/download PDF
9. Copper(II) sulfonamide complexes having enzyme inhibition activities on carbonic anhydrase I: synthesis, characterization and inhibition studies.
- Author
-
Uzun, Demet, Balaban Gündüzalp, Ayla, Parlakgümüş, Gökhan, Özmen, Ümmühan Özdemir, Özbek, Neslihan, and Aktan, Ebru
- Subjects
- *
CARBONIC anhydrase , *MULTIENZYME complexes , *COPPER compounds , *SULFONAMIDES , *COPPER , *SULFONIC acids - Abstract
In our present study, copper(II) sulfonamide complexes titled as bis-(2 acetylfuranmethanesulfonylhydrazone) copper(II) chloride, bis-(2-furaldehydemethanesulfonylhydrazone)copper(II) chloride and bis-(5-nitro-2 furaldehydemethanesulfonylhydrazone)copper(II) chloride were synthesized using aromatic sulfonylhydrazones derived from methane sulfonic acid hydrazide. The structures of copper(II) sulfonamides were determined by using LC–MS, FT-IR and UV–Vis methods, magnetism and conductivity measurements, and also electrochemical studies. In order to gain insight into the structure of the copper(II) complexes, computational studies were performed by using DFT/B3LYP/6-311G(d,p) basis set with the Gaussian 09 program package. In general, sulfonamides and their derivatives are researched for their inhibitory effects on carbonic anhydrase isoenzymes (CAs). Synthesized copper(II) complexes have also sulfonamide group which is the most important pharmacophore for CA inhibition efficiency like acetazolamide (AAZ) as positive control. The carbonic anhydrase I (CA I) inhibition of copper(II) complexes which goes on competitively was determined by using UV–Vis spectrophotometer technique, and their inhibition parameters such as Km, IC50 and Ki were calculated. Among tested compounds, bis-(5-nitro-2 furaldehydemethanesulfonylhydrazone) copper(II) chloride was found to be the most active complex on CA I isoenzyme with IC50 value of 7.03 × 10−5 M. The enzyme inhibition trends of copper(II) sulfonamides on CA I isoenzyme were also investigated by CV and differential pulse voltammetry (DPV) techniques, qualitatively. The substrate of p-nitrophenyl acetate (PNPA) was hydrolyzed by CA I and produced p-nitrophenol (PNP). The electrochemical studies showed that when the concentration of the inhibitor was increased, the reduction peak current of PNP produced by the hydrolysis of PNPA was decreased by enzyme inhibition. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
10. Exploring the multi-target enzyme inhibition potential of new sulfonamido-thiazoline derivatives; synthesis and computational studies
- Author
-
Imran Shafique, Aamer Saeed, Atteeque Ahmed, Ghulam Shabir, Anwar Ul-Hamıd, Ajmal Khan, Burak Tüzün, Mahinur Kirici, Parham Taslimi, and Muhammad Latif
- Subjects
Nimesulide ,Acetylcholinesterase ,Butyrylcholinesterase ,Carbonic anhydrase I ,Carbonic anhydrase II ,Enzyme inhibition ,Chemistry ,QD1-999 - Abstract
A small library of ten new Nimesulide-iminothiazolines conjugates was synthesized by the reduction of nitro group of Nimesulide followed by conversion into variously substituted acyl thioureas. Heterocyclization of the latter with phenacyl bromide afforded the products (7a-j) in good to excellent yields and high purity. The newly synthezied (7a-j) were screend for inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), carbonic anhydrase I (hCA I) and carbonic anhydrase II (hCA II). Most of the synthesized molecules were more effective than standard inhibitors tacrine, and acetazolamide against AchE, BchE and against CA I and CA II respectively. Compounds 7 h, 7f, 7d and 7i were the most potent compounds against hCA I&II. Whilst compounds 7a, 7d and 7f showed highest inhibition against acetylcholinesterase (AChE), butyrylcholinesterase (BChE) when compared with standard inhibitor Tacrine. In silico studies were also performed to find the type of interactions. Molecular docking was accomplished to explore the putative binding mode of interactions of selective inhibitors. Finally, the ADMET analysis of the molecules was also performed.
- Published
- 2022
- Full Text
- View/download PDF
11. Synthesis, molecular docking analysis, drug-likeness evaluation, and inhibition potency of new pyrazole-3,4-dicarboxamides incorporating sulfonamide moiety as carbonic anhydrase inhibitors.
- Author
-
Özkul Ş, Tunca E, Mert S, Bayrakdar A, and Kasımoğulları R
- Subjects
- Humans, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Carbonic Anhydrase II, Spectroscopy, Fourier Transform Infrared, Pyrazoles chemistry, Sulfonamides chemistry, Isoenzymes, Sulfanilamide, Carbonic Anhydrase Inhibitors chemistry, Carbonic Anhydrase I
- Abstract
A series of novel pyrazole-dicarboxamides were synthesized from pyrazole-3,4-dicarboxylic acid chloride and various primary and secondary sulfonamides. The structures of the new compounds were confirmed by FT-IR,
1 H-NMR,13 C-NMR, and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.024-0.496 µM for hCA I and 0.006-5.441 µM for hCA II. Compounds 7a and 7i showed nanomolar level of inhibition of hCA II, and these compounds exhibited high selectivity for this isoenzyme. Molecular docking studies were performed between the most active compounds 7a, 7b, 7i, and the reference inhibitor AAZ and the hCAI and hCAII to investigate the binding mechanisms between the compounds and the isozymes. These compounds showed better interactions than the AAZ. ADMET and drug-likeness analyses for the compounds have shown that the compounds can be used pharmacologically in living organisms., (© 2024 Wiley Periodicals LLC.)- Published
- 2024
- Full Text
- View/download PDF
12. New N -(1,3,4-thiadiazole-2-yl)acetamide derivatives as human carbonic anhydrase I and II and acetylcholinesterase inhibitors.
- Author
-
Dawbaa S, Türkeş C, Nuha D, Demir Y, Evren AE, Yurttaş L, and Beydemir Ş
- Abstract
Various carbonic anhydrase (CA) enzyme isoforms are known today. In addition to the use of CA inhibitors as diuretics, antiepileptics and antiglaucoma agents, the inhibition of other specific isoforms of CA was reported to have clinical benefits in cancers. In this study, two groups of 1,3,4-thiadiazole derivatives were designed and synthesized to act as human CA I and II ( h CA I and h CA II) inhibitors. The activities of these compounds were tested in vitro and evaluated in silico studies. The activity of the synthesized compounds was also tested against acetylcholinesterase (AChE) to evaluate the relation of the newly designed structures to the activity against AChE. The synthesized compounds were analyzed by
1 H NMR,13 C NMR and high-resolution mass spectroscopy (HRMS). The results displayed a better activity of all the synthesized compounds against h CA I than that of the commonly used standard drug, Acetazolamide (AAZ). The compounds also showed better activity against h CA II, except for compounds 5b and 6b . Only compounds 6a and 6c showed superior activity against AChE compared to the standard agent, tacrine (THA). In silico studies, including absorption, distribution, metabolism and excretion (ADME) and drug-likeness evaluation, molecular docking, molecular dynamic simulations (MDSs) and density functional theory (DFT) calculations, were compatible with the in vitro results and presented details regarding the structure-activity relationship.Communicated by Ramaswamy H. Sarma.- Published
- 2024
- Full Text
- View/download PDF
13. Novel 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide based thiosemicarbazides as potent and selective inhibitors of tumor-associated human carbonic anhydrase IX and XII: Synthesis, cytotoxicity, and molecular modelling studies.
- Author
-
Demir-Yazıcı K, Trawally M, Bua S, Öztürk-Civelek D, Akdemir A, Supuran CT, and Güzel-Akdemir Ö
- Subjects
- Humans, Carbonic Anhydrase IX, Structure-Activity Relationship, Sulfonamides pharmacology, Sulfonamides chemistry, Antigens, Neoplasm metabolism, Carbonic Anhydrase I, Protein Isoforms metabolism, Indoles pharmacology, Molecular Structure, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Neoplasms, Semicarbazides
- Abstract
In the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to ∼340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (K
i ) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; Ki : 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC50 : 53.32 ± 7.74 µM for HT-29; IC50 : 74.64 ± 14.15 µM for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
14. Researchers from Bilecik Seyh Edebali University Report Recent Findings in Alzheimer Disease (Functionalized methoxy quinoline derivatives: Experimental and in silico evaluation as new antiepileptic, anti-Alzheimer, antibacterial and antifungal...).
- Abstract
Researchers from Bilecik Seyh Edebali University have conducted a study on newly synthesized quinoline derivatives and their inhibitory effects on human carbonic anhydrase I and II (hCA I and II) enzymes, as well as acetylcholinesterase (AChE) enzymes. The study also examined the impact of these derivatives on various microorganisms. The results showed that several compounds exhibited strong inhibitory effects on hCA I and II and AChE enzymes, as well as promising antimicrobial activity. The study concluded that these findings provide valuable insights into the structure-activity relationships of quinoline derivatives and identify potential candidates for further research in enzyme inhibition and antimicrobial studies. [Extracted from the article]
- Published
- 2024
15. Overexpression of CA1 mRNA and the CA I Protein in Tumor Cells Does Not Change the Gene Expression of the ECM Proteins.
- Author
-
Lakota, Ján and Dubrováková, Mária
- Subjects
- *
TUMOR proteins , *GENE expression , *AUTOANTIBODIES , *EXTRACELLULAR matrix proteins , *PROTEIN expression , *CARBONIC anhydrase - Abstract
In our study, we performed retroviral transduction to overexpress codon-optimized variant of gene encoding human carbonic anhydrase I (optiCA1) in two tumor cell lines PC3 and MDA-MB-231, derived from human prostatic and breast carcinoma respectively. We achieved significantly enhanced and stable overexpression of exogenous optiCA1 gene. The expression of endogenous, wild CA1 gene was found to be normally low (Ct28.6 for PC3 cells) or below to the detection limit (Ct 35.5 for MDA-MB-231 cells). No morphological changes and no decreasing viability of tumor cells were observed upon stable overexpression of the optiCA1 gene. In our study we have shown that the overexpression of the optimized human CA1 in engineered PC3 and MDA-MB-231 cells did not induce similar changes as we observed in tumor cells cultivated in the presence of human sera containing extensively high titers of anti-CA I autoantibodies from patients with complete remission of malignant disease. In both optiCA1transduced cell lines, the expression of selected genes responsible for basal lamina assembly, cytoskeleton, extracellular matrix proteins and proto-oncogenes (COL1A1, COL4A4, LAMC2, CTHRC1, and WNT7B) was not changed. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
16. The Relationship between Serum Carbonic Anhydrase I-II Autoantibody Levels and Diabetic Retinopathy in Type 1 Diabetes Patients
- Author
-
Adem Türk, Süleyman Mollamehmetoğlu, Ahmet Alver, Ahmet Menteşe, İrfan Nuhoğlu, Cihangir Erem, and Halil İbrahim İmamoğlu
- Subjects
Carbonic anhydrase I ,carbonic anhydrase II ,diabetes mellitus ,diabetic retinopathy ,Medicine ,Ophthalmology ,RE1-994 - Abstract
Objectives: To investigate the relationship between serum carbonic anhydrase I-II (CA-I and II) autoantibody levels and diabetic retinopathy (DRP) in cases with type 1 diabetes. Materials and Methods: A total of 37 type-1 diabetic patients, 17 with DRP (group 1) and 20 without (group 2), and 38 healthy control subjects (group 3) were included. CA-I and CA-II autoantibody levels were measured in serum samples obtained from each of the three groups and compared statistically. Additionally, the correlation between CA-I and CA-II autoantibody levels and the presence of diabetic macular edema was examined. Results: Mean measured CA-I autoantibody levels were 0.145±0.072, 0.117±0.047, and 0.138±0.061 ABSU in group 1, group 2, and group 3, respectively (p=0.327). The average CA-II autoantibody levels achieved in the same groups were 0.253±0.174, 0.155±0.137, and 0.131±0.085 ABSU, respectively (p=0.005). No significant difference was obtained between the subgroups of group 1, with macular edema (n=8) and without (n=9), in terms of both CA-I and CA-II autoantibody levels (p=0.501, p=0.178, respectively). Conclusion: A significant correlation was observed between the development of DRP and serum CA-II autoantibody levels in type-1 diabetic cases. However, there was no correlation between the autoantibody levels and the presence of diabetic macular edema in cases with DRP.
- Published
- 2017
- Full Text
- View/download PDF
17. Click chemistry‐based synthesis of new benzenesulfonamide derivatives bearing triazole ring as selective carbonic anhydrase II inhibitors
- Author
-
Ewies F. Ewies, Eman Sabry, Mohamed S. Bekheit, Marwa A. Fouad, Daniela Vullo, and Claudiu T. Supuran
- Subjects
Structure-Activity Relationship ,Sulfonamides ,Zinc ,Carbonic Anhydrase I ,Molecular Structure ,Drug Discovery ,Humans ,Protein Isoforms ,Click Chemistry ,Triazoles ,Carbonic Anhydrase Inhibitors ,Carbonic Anhydrase II ,Carbonic Anhydrases - Abstract
A series of 1,2,3-triazol-1-ylbenzenesulfonamide derivatives was designed, synthesized and their ability to inhibit several carbonic anhydrase isoforms was evaluated. The basis of our design is to hybridize the benzenesulfonamide moiety widely used as a zinc-binding group, a triazole ring as spacer with a tail of different substituted aryl moieties. The synthesis of these compounds was achieved using Cu(I)-mediated click chemistry between the azide containing the benzenesulfonamide pharmacophore and various aryl acetylenes or 1,6-heptadiyne through copper-catalyzed [3+2] cycloaddition reaction. The ability the new derivatives to inhibit four human carbonic anhydrase isoforms hCA I, II, IX, and XII was evaluated. All the compounds exhibited good potency and high selectivity towards isoforms hCA I and II more than isoforms hCA IX and XII, especially for the derivatives 3c and 3j that displayed K
- Published
- 2022
18. Benzimidazolium Salts Bearing Nitrile Moieties: Synthesis, Enzyme Inhibition Profiling, and Molecular Docking Analysis for Carbonic Anhydrase and Acetylcholinesterase.
- Author
-
Öner E, Gök Y, Demir Y, Taskin-Tok T, Aktaş A, Gülçin İ, and Yalın S
- Subjects
- Acetylcholinesterase metabolism, Molecular Docking Simulation, Salts pharmacology, Carbonic Anhydrase II, Spectroscopy, Fourier Transform Infrared, Cholinesterase Inhibitors chemistry, Carbonic Anhydrase I, Benzimidazoles, Nitrogen, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Structure-Activity Relationship, Molecular Structure, Carbonic Anhydrases metabolism
- Abstract
This report presents the synthesis and characterization of a range of benzimidazolium salts featuring 3-cyanopropyl groups on the 1
st nitrogen atom and varied alkyl groups on the 3rd nitrogen atom within the benzimidazole structure. Benzimidazolium salts were synthesized by N-alkylation of 1-alkyl benzimidazole with 3-cyanopropyl-bromide. The new salts were characterized by1 H and13 C-NMR, FT-IR spectroscopic and elemental analysis techniques. In this study, the enzyme inhibition abilities of seven nitrile substituted benzimidazolium salts were investigated against acetylcholinesterase (AChE) and carbonic anhydrase isoenzymes I and II (hCA I and hCA II). They showed a highly potent inhibition effect on AChE, hCA I and hCA II (Ki values are in the range of 26.71-119.09 nM for AChE, 19.77 to 133.68 nM for hCA I and 13.09 to 266.38 nM for hCA II). Reflecting the binding mode of the synthesized cyanopropyl series, the importance of the 2,3,5,6-tetramethylbenzyl, 3-methylbenzyl and 3-benzyl groups for optimal interactions with target proteins, evaluated by molecular docking studies. At the same time, the docking findings support the inhibition constants (Ki ) values of the related compounds in this study. Potential compounds were also evaluated by their pharmacokinetic properties were predicted., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)- Published
- 2023
- Full Text
- View/download PDF
19. Inhibitory effects of sulfenimides on human and bovine carbonic anhydrase enzymes.
- Author
-
Yakan H, Bilir G, Çakmak Ş, Taş Ö, Türköz Karakullukçu N, Soydan E, Kütük H, Güçlü C, Şentürk M, Arslan T, Öztürk S, Aksakal E, and Ekinci D
- Subjects
- Humans, Cattle, Animals, Structure-Activity Relationship, Carbonic Anhydrase I, Carbonic Anhydrase II, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Molecular Structure, Carbonic Anhydrases chemistry
- Abstract
A series of sulfenimide derivatives (1a-i) were investigated as inhibitors of human (hCA-I, hCA-II) and bovine (bCA) carbonic anhydrase enzymes. The compounds were synthesised by the reaction of substituted thiophenols with phthalimide by means of an effective, simple and eco-friendly method and the structures were confirmed by IR,
1 H NMR,13 C NMR, MS and elemental analysis. All derivatives except for the methyl derivative ( 1b ) exhibited effective inhibitory action at low micromolar concentrations on human isoforms, but only four derivatives ( 1e , 1f , 1h , 1i ) inhibited the bovine enzyme. The bromo derivative ( 1f) was found to be strongest inhibitor of all three enzymes with KI values of 0.023, 0.044 and 20.57 µM for hCA-I, hCA-II and bCA, respectively. Results of our study will make valuable contributions to carbonic anhydrase inhibition studies for further investigations since inhibitors of this enzyme are important molecules for medicinal chemistry.- Published
- 2023
- Full Text
- View/download PDF
20. Carbonic anhydrase inhibitory activity of phthalimide-capped benzene sulphonamide derivatives.
- Author
-
Shilkar D, Mohd Siddique MU, Bua S, Yasmin S, Patil M, Timiri AK, Supuran CT, and Jayaprakash V
- Subjects
- Molecular Structure, Structure-Activity Relationship, Carbonic Anhydrase I, Carbonic Anhydrase II, Molecular Docking Simulation, Benzene Derivatives, Carbonic Anhydrase Inhibitors pharmacology, Sulfonamides pharmacology, Phthalimides pharmacology, Benzene, Carbonic Anhydrases metabolism
- Abstract
A series of phthalimide-capped benzene sulphonamides ( 1 - 22 ) reported by our group for dengue protease inhibitory activity have been evaluated for their carbonic anhydrase (hCA, EC 4.2.1.1) inhibitory activity against hCA I, hCA II. Compounds 1 , 3 , 10 , and 15 showed hCA I inhibition, whereas 1 , 4 , and 10 showed hCA II inhibition at nanomolar concentrations. Among these compounds, 1 displayed potent inhibitory activity against the hCA I (Ki = 28.5 nM) and hCA II (Ki = 2.2 nM), being 10 and 6 times more potent than acetazolamide, a standard inhibitor (Ki = 250 nM and 12 nM), respectively. Furthermore, this compound displayed 14-fold selectivity towards the hCA II isoform compared to hCA I. Molecular docking and MD simulations were performed to understand the atomic level interactions responsible for the selectivity of compound 1 towards hCA II.
- Published
- 2023
- Full Text
- View/download PDF
21. Aryl derivatives of 3 H -1,2-benzoxaphosphepine 2-oxides as inhibitors of cancer-related carbonic anhydrase isoforms IX and XII.
- Author
-
Balašova A, Pustenko A, Nocentini A, Vullo D, Supuran CT, and Žalubovskis R
- Subjects
- Carbonic Anhydrase I, Cytosol, Oxides, Protein Isoforms, Carbonic Anhydrases, Neoplasms
- Abstract
A range of 3 H -1,2-benzoxaphosphepine 2-oxide aryl derivatives with various substitution patterns at positions 7, 8, or 9 of the scaffold was synthesised in five steps from the commercially available salicylaldehydes. All of the newly obtained compounds were studied for their inhibition potency against carbonic anhydrase (CA) isoforms I, II, IX, and XII. Delightfully, these compounds showed a striking selectivity for the cancer-associated CA IX and XII over the cytosolic CA I and II, whose inhibition may lead to side-effects. Overall, a structure-activity relationship (SAR) revealed that 7- and 8-substituted aryl derivatives were more effective inhibitors of CA IX and XII than 9-substituted derivatives. In addition, the fluorine-containing analogues emerged as the most potent CA IX/XII inhibitors in this series.
- Published
- 2023
- Full Text
- View/download PDF
22. 2H-chromene and 7H-furo-chromene derivatives selectively inhibit tumour associated human carbonic anhydrase IX and XII isoforms.
- Author
-
Sequeira L, Distinto S, Meleddu R, Gaspari M, Angeli A, Cottiglia F, Secci D, Onali A, Sanna E, Borges F, Uriarte E, Alcaro S, Supuran CT, and Maccioni E
- Subjects
- Humans, Carbonic Anhydrase IX, Carbonic Anhydrase I, Carbonic Anhydrase II, Structure-Activity Relationship, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Antigens, Neoplasm chemistry, Benzopyrans pharmacology, Isoenzymes metabolism, Molecular Structure, Carbonic Anhydrases metabolism, Neoplasms drug therapy, Neoplasms pathology
- Abstract
Tumour associated carbonic anhydrases (CAs) IX and XII have been recognised as potential targets for the treatment of hypoxic tumours. Therefore, considering the high pharmacological potential of the chromene scaffold as selective ligand of the IX and XII isoforms, two libraries of compounds, namely 2H-chromene and 7H-furo-chromene derivatives, with diverse substitution patterns were designed and synthesised. The structure of the newly synthesised compounds was characterised and their inhibitory potency and selectivity towards human CA off target isoforms I, II and cancer-associated CA isoforms IX and XII were evaluated. Most of the compounds inhibit CA isoforms IX and XII with no activity against the I and II isozymes. Thus, while the potency was influenced by the substitution pattern along the chromene scaffold, the selectivity was conserved along the series, confirming the high potential of both 2H-chromene and 7H-furo-chromene scaffolds for the design of isozyme selective inhibitors.
- Published
- 2023
- Full Text
- View/download PDF
23. Investigation of novel alkyl/benzyl (4-sulphamoylphenyl)carbamimidothioates as carbonic anhydrase inhibitors.
- Author
-
Abdoli M, Bonardi A, Supuran CT, and Žalubovskis R
- Subjects
- Humans, Carbonic Anhydrase I, Carbonic Anhydrase II, Protein Isoforms, Structure-Activity Relationship, Carbonic Anhydrase IX, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism
- Abstract
A library of novel alkyl/benzyl (4-sulphamoylphenyl)carbamimidothioates was synthesised by selective S -alkylation of the easily accessible 4-thioureidobenzenesulphonamide. The compounds were assayed as inhibitors of four human (h) carbonic anhydrase isoforms hCA I, II, VII, and XIII, as well as three bacterial enzymes belonging to the β-CA class, MscCA from Mammaliicoccus ( Staphylococcus ) sciuri and StCA1 and StCA2, from Salmonella enterica (serovar Typhimurium ). Most compounds investigated here exhibited moderate to low nanomolar inhibition constants against hCA I, II, and VII. The cytosolic hCA XIII was also inhibited by these compounds, but not as effective as hCA I, II, and VII. Several compounds were very effective against MscCA and StCA1. StCA2 was less inhibited compared to MscCA and StCA1. Some compounds showed considerable selectivity for inhibiting some CA isoforms. They may thus be considered as interesting starting points for the discovery and development of novel therapeutic agents belonging to this class of enzyme inhibitors.
- Published
- 2023
- Full Text
- View/download PDF
24. Potent carbonic anhydrase I, II, IX and XII inhibition activity of novel primary benzenesulfonamides incorporating bis-ureido moieties.
- Author
-
Tekeli T, Akocak S, Petreni A, Lolak N, Çete S, and Supuran CT
- Subjects
- Humans, Isocyanates, Sulfonamides pharmacology, Benzenesulfonamides, Carbonic Anhydrase I, Carbonic Anhydrases
- Abstract
A novel series of twelve aromatic bis-ureido-substituted benzenesulfonamides was synthesised by conjugation of aromatic aminobenzenesulfonamides with aromatic bis-isocyanates. The obtained bis-ureido-substituted derivatives were tested against four selected human carbonic anhydrase isoforms (hCA I, hCA II, hCA IX and hCA XII). Most of the new compounds showed an effective inhibitory profile against isoforms hCA IX and hCA XII, also having some selectivity with respect to hCA I and hCA II. The inhibition constants of these compounds against isoforms hCA IX and XII were in the range of 6.73-835 and 5.02-429 nM, respectively. Since hCA IX and hCA XII are important drug targets for anti-cancer/anti-metastatic drugs, these effective inhibitors reported here may be considered of interest for cancer related studies in which these enzymes are involved.
- Published
- 2023
- Full Text
- View/download PDF
25. 3 H -1,2-Benzoxaphosphepine 2-oxides as selective inhibitors of carbonic anhydrase IX and XII.
- Author
-
Pustenko A, Balašova A, Nocentini A, Supuran CT, and Žalubovskis R
- Subjects
- Humans, Carbonic Anhydrase IX metabolism, Structure-Activity Relationship, Carbonic Anhydrase I, Antigens, Neoplasm, Molecular Structure, Carbonic Anhydrase Inhibitors pharmacology, Oxides
- Abstract
The synthesis of 3 H -1,2-benzoxaphosphepine 2-oxides and evaluation of their inhibitory activity against human carbonic anhydrase (hCA) isoforms I, II, IX, and XII are described. The target compounds were obtained via a concise synthesis from commercial salicylaldehydes and displayed low to sub-micromolar inhibition levels against the tumour-associated isoforms hCA IX and XII. All obtained benzoxaphosphepine 2-oxides possess remarkable selectivity for inhibition of hCA IX/XII over the off-target cytosolic hCA isoforms I and II, whose inhibition may lead to side effects.
- Published
- 2023
- Full Text
- View/download PDF
26. Ureidobenzenesulfonamides as Selective Carbonic Anhydrase I, IX, and XII Inhibitors.
- Author
-
Denner TC, Angeli A, Ferraroni M, Supuran CT, and Csuk R
- Subjects
- Carbonic Anhydrase IX, Structure-Activity Relationship, Carbonic Anhydrase Inhibitors pharmacology, Sulfonamides pharmacology, Molecular Structure, Antigens, Neoplasm, Carbonic Anhydrase I, Carbonic Anhydrases metabolism
- Abstract
Sulfonamides remain an important class of drugs, especially because of their inhibitory effects on carbonic anhydrases. Herein, we have synthesized several sulfonamides and tested them for their inhibitory activity against carbonic anhydrases hCA I, hCA II, hCA IX, and hCA XII, respectively. Thereby, biphenyl- and benzylphenyl-substituted sulfonamides showed high selectivity against hCA IX and hCA XII; these enzymes are common targets in the treatment of hypoxic cancers, and noteworthy inhibitory activity was observed for several compounds toward hCA I that might be of interest for future applications to treat cerebral edema. Compound 3 (4-[3-(2-benzylphenyl)ureido]benzenesulfonamide) held an exceptionally low K
i value of 1.0 nM for hCA XII.- Published
- 2023
- Full Text
- View/download PDF
27. Potent inhibitors of tumor associated carbonic anhydrases endowed with cathepsin B inhibition.
- Author
-
Kumar A, Arya P, Sharma V, Giovannuzzi S, Raghav N, Supuran CT, and Sharma PK
- Subjects
- Humans, Acetazolamide pharmacology, Cathepsin B, Structure-Activity Relationship, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase I, Protein Isoforms, Molecular Structure, Carbonic Anhydrases metabolism, Neoplasms
- Abstract
Twenty-one novel extended analogs of acetazolamide were synthesized and screened in vitro for their inhibition efficacy against human carbonic anhydrase (hCA) isoforms I, II, IX, XII, and cathepsin B. The majority of the compounds were found to be effective inhibitors of tumor-associated hCA IX and XII, and poor inhibitors of cytosolic hCA I. Despite the strong to moderate inhibition potential possessed by these compounds toward another cytosolic isoform hCA II, some of them demonstrated better potency against hCA IX and/or XII isoforms as compared to hCA II. Four compounds (11f, 11g, 12c, and 12g) effectively inhibited hCA IX and/or XII isoforms with considerable selectivity over the off-targets hCA I and II. Interestingly, five compounds, including 11f, 11g, 12c, 12d, and 12g, inhibited hCA IX even better than the clinically used acetazolamide. Some of the novel synthesized compounds exhibited higher anti-cathepsin B potential than acetazolamide, with % inhibition of around 50%, at a concentration of 10
-7 M. Further, two compounds (12g and 12c) that showed effective and selective inhibition activity profiles against hCA IX and XII were additionally found to be effective inhibitors of cathepsin B., (© 2023 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2023
- Full Text
- View/download PDF
28. Exploration of 3-aryl pyrazole-tethered sulfamoyl carboxamides as carbonic anhydrase inhibitors.
- Author
-
Ommi O, Paoletti N, Bonardi A, Gratteri P, Bhalerao HA, Sau S, Nanduri S, Mohammed A, Kalia NP, Sonti R, Supuran CT, and Yaddanapudi VM
- Subjects
- Humans, Structure-Activity Relationship, Carbonic Anhydrase II, Pyrazoles pharmacology, Carbonic Anhydrase I, Sulfonamides pharmacology, Benzamides, Molecular Structure, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrases metabolism
- Abstract
Herein, we report the design and synthesis of two series of pyrazole-tethered sulfamoyl phenyl acetamides and pyrazole-tethered sulfamoyl phenyl benzamides. The synthesized compounds were investigated for inhibiting two human carbonic anhydrases, human carbonic anhydrases (hCA) I and II, and those of the bacterial pathogen Mycobacterium tuberculosis, mtCA 1-3. The results indicate that, among the synthesized compounds, pyrazoles with 4-aminobenzene sulfonamide were more selective toward hCA I and II over mtCAs, and compounds with 3-aminobenzene sulfonamide were selective toward mtCA 1-3 over hCA I, II. Compound 6g showed significant and selective inhibition toward hCA I and II, with K
i values of 0.0366 and 0.0310 µM, respectively. Compound 5g exhibited the best inhibition toward mtCA 2, with a Ki value of 0.0617 µM. Among the benzamides, compound 9b exhibited significant activity toward mtCA 2, with a Ki value of 0.0696 µM. Selectivity of these compounds was further supported by docking studies. When tested for antitubercular activity, many compounds showed moderate to good inhibition against the Mtb H37Rv strain, with minimum inhibitory concentration (MIC) values in the range of 4-128 µg/mL., (© 2023 Deutsche Pharmazeutische Gesellschaft.)- Published
- 2023
- Full Text
- View/download PDF
29. Synthesis, Theoretical, in Silico and in Vitro Biological Evaluation Studies of New Thiosemicarbazones as Enzyme Inhibitors.
- Author
-
Erdoğan M, Serdar Çavuş M, Muğlu H, Yakan H, Türkeş C, Demir Y, and Beydemir Ş
- Subjects
- Structure-Activity Relationship, Molecular Docking Simulation, Cholinesterase Inhibitors chemistry, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Acetylcholinesterase metabolism, Spectroscopy, Fourier Transform Infrared, Carbonic Anhydrase I, Enzyme Inhibitors chemistry, Molecular Structure, Isothiocyanates, Thiosemicarbazones chemistry
- Abstract
Eleven new thiosemicarbazone derivatives (1-11) were designed from nine different biologically and pharmacologically important isothiocyanate derivatives containing functional groups such as fluorine, chlorine, methoxy, methyl, and nitro at various positions of the phenyl ring, in addition to the benzyl unit in the molecular skeletal structure. First, their substituted-thiosemicarbazide derivatives were synthesized from the treatment of isothiocyanate with hydrazine to synthesize the designed compounds. Through a one-step easy synthesis and an eco-friendly process, the designed compounds were synthesized with yields of up to 95 % from the treatment of the thiosemicarbazides with aldehyde derivatives having methoxy and hydroxy groups. The structures of the synthesized molecules were elucidated with elemental analysis and FT-IR,
1 H-NMR, and13 C-NMR spectroscopic methods. The electronic and spectroscopic properties of the compounds were determined by the DFT calculations performed at the B3LYP/6-311++G(2d,2p) level of theory, and the experimental findings were supported. The effects of some global reactivity parameters and nucleophilic-electrophilic attack abilities of the compounds on the enzyme inhibition properties were also investigated. They exhibited a highly potent inhibition effect on acetylcholinesterase (AChE) and carbonic anhydrases (hCAs) (KI values are in the range of 23.54±4.34 to 185.90±26.16 nM, 103.90±23.49 to 325.90±77.99 nM, and 86.15±18.58 to 287.70±43.09 nM for AChE, hCA I, and hCA II, respectively). Furthermore, molecular docking simulations were performed to explain each enzyme-ligand complex's interaction., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)- Published
- 2023
- Full Text
- View/download PDF
30. Piperazin incorporated Schiff Base derivatives: Assessment of in vitro biological activities, metabolic enzyme inhibition properties, and molecular docking calculations.
- Author
-
Mermer A, Tüzün B, Daştan SD, Koçyiğit ÜM, Çetin FN, and Çevik Ö
- Subjects
- Mice, Animals, Humans, Female, Molecular Docking Simulation, Molecular Structure, Structure-Activity Relationship, Carbonic Anhydrase Inhibitors pharmacology, Carbonic Anhydrase Inhibitors chemistry, Schiff Bases pharmacology, Carbonic Anhydrase I, Antineoplastic Agents pharmacology, Antineoplastic Agents chemistry, Breast Neoplasms
- Abstract
The cytotoxic activities of the compounds were determined by the 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) method in human breast cancer (MCF-7), human cervical cancer (HeLa), and mouse fibroblast (L929) cell lines. The compounds MAAS-5 and four modified the supercoiled tertiary structure of pBR322 plasmid DNA. MAAS-5 showed the highest cytotoxic activity in HeLa, MCF-7, and L929 cells with IC50 values of 16.76 ± 3.22, 28.83 ± 5.61, and 2.18 ± 1.22 µM, respectively. MAAS-3 was found to have almost the lowest cytotoxic activities with the IC50 values of 93.17 ± 9.28, 181.07 ± 11.54, and 16.86 ± 6.42 µM in HeLa, MCF-7, and L929 cells respectively at 24 h. Moreover, the antiepileptic potentials of these compounds were investigated in this study. To this end, the effect of newly synthesized Schiff base derivatives on the enzyme activities of carbonic anhydrase I and II isozymes (human carbonic anhydrase [hCA] I and hCA II) was evaluated spectrophotometrically. The target compounds demonstrated high inhibitory activities compared with standard inhibitors with K
i values in the range of 4.54 ± 0.86-15.46 ± 8.65 nM for hCA I (Ki value for standard inhibitor = 12.08 ± 2.00 nM), 1.09 ± 0.32-29.94 ± 0.82 nM for hCA II (Ki value for standard inhibitor = 18.22 ± 4.90 nM). Finally, the activities of the compounds were compared with the Gaussian programme in the B3lyp, HF, M062X base sets with 6-31++G (d,p) levels. In addition, the activities of five compounds against various breast cancer proteins and hCA I and II were compared with molecular docking calculations. Also, absorption, distribution, metabolism, excretion, and toxicity analysis was performed to investigate the possibility of using five compounds as drug candidates., (© 2023 Wiley Periodicals LLC.)- Published
- 2023
- Full Text
- View/download PDF
31. Physiological Functions of the Alpha Class of Carbonic Anhydrases
- Author
-
Frost, Susan C., Harris, J. Robin, Series editor, Frost, Susan C., editor, and McKenna, Robert, editor
- Published
- 2014
- Full Text
- View/download PDF
32. Silencing of carbonic anhydrase I enhances the malignant potential of exosomes secreted by prostatic tumour cells.
- Author
-
Bánová Vulić, Radivojka, Zdurienčíková, Martina, Tyčiaková, Silvia, Benada, Oldřich, Dubrovčáková, Mária, Lakota, Ján, and Škultéty, Ľudovít
- Subjects
EXOSOMES ,CARBONIC anhydrase ,MASS analysis (Spectrometry) ,CELL anatomy ,TUMORS ,CELLS - Abstract
We report results showing that the silencing of carbonic anhydrase I (siCA1) in prostatic (PC3) tumour cells has a significant impact on exosome formation. An increased diameter, concentration and diversity of the produced exosomes were noticed as a consequence of this knock‐down. The protein composition of the exosomes' cargo was also altered. Liquid chromatography and mass spectrometry analyses identified 42 proteins significantly altered in PC3 siCA1 exosomes compared with controls. The affected proteins are mainly involved in metabolic processes, biogenesis, cell component organization and defense/immunity. Interestingly, almost all of them have been described as 'enhancers' of tumour development through the promotion of cell proliferation, migration and invasion. Thus, our results indicate that the reduced expression of the CA1 protein enhances the malignant potential of PC3 cells. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
33. New Pd(II) complexes of the bisthiocarbohydrazones derived from isatin and disubstituted salicylaldehydes: Synthesis, characterization, crystal structures and inhibitory properties against some metabolic enzymes
- Author
-
Yeliz Kaya, Ayşe Erçağ, Yunus Zorlu, Yeliz Demir, and İlhami Gülçin
- Subjects
Isatin ,Inorganic Chemistry ,Structure-Activity Relationship ,Carbonic Anhydrase I ,Molecular Structure ,Acetylcholinesterase ,Cholinesterase Inhibitors ,Carbonic Anhydrase Inhibitors ,Ligands ,Carbonic Anhydrase II ,Biochemistry - Abstract
Pd(II) complexes (Pd1, Pd2, and Pd3) were synthesized for the first time using asymmetric isatin bisthiocarbohydrazone ligands and PdCl
- Published
- 2022
34. In vitro and in silico interactions of antiulcer, glucocorticoids and urological drugs on human carbonic anhydrase I and II isozymes
- Author
-
Uğur Güller, Şükrü Beydemir, and Ömer İrfan Küfrevioğlu
- Subjects
Isoenzymes ,Molecular Docking Simulation ,Pharmacology ,Structure-Activity Relationship ,Carbonic Anhydrase I ,Humans ,Pharmaceutical Science ,Pharmacology (medical) ,General Medicine ,Budesonide ,Carbonic Anhydrase Inhibitors ,Carbonic Anhydrase II ,Glucocorticoids - Abstract
Carbonic anhydrases (CAs, Enzyme Commission 4.2.1.1) convert carbon dioxide to bicarbonate in metabolism and use Zn
- Published
- 2022
35. Researchers from Adiyaman University Detail Findings in Enzyme Inhibition and Medicinal Chemistry (Potent carbonic anhydrase I, II, IX and XII inhibition activity of novel primary benzenesulfonamides incorporating bis-ureido moieties).
- Abstract
A recent study conducted by researchers from Adiyaman University focused on enzyme inhibition and medicinal chemistry. The study involved the synthesis of a series of twelve aromatic bis-ureido-substituted benzenesulfonamides and their testing against four human carbonic anhydrase isoforms. The compounds showed effective inhibitory activity against isoforms hCA IX and hCA XII, which are important drug targets for anti-cancer/anti-metastatic drugs. The findings suggest that these inhibitors may be of interest for cancer-related studies involving these enzymes. [Extracted from the article]
- Published
- 2023
36. Effects of mechanical stress and deficiency of dihydrotestosterone or 17β-estradiol on Temporomandibular Joint Osteoarthritis in mice
- Author
-
Katsuhiko Amano, Kenji Sueishi, Masashi Nagao, Yoichi Ishizuka, Akira Watanabe, Takenobu Ishii, Tomohisa Ootake, Yasushi Nishii, and Kazuaki Nishimura
- Subjects
Male ,medicine.medical_specialty ,Carbonic Anhydrase I ,Ovariectomy ,Biomedical Engineering ,Osteoclasts ,Osteoarthritis ,Chondrocyte ,Condyle ,Chondrocytes ,stomatognathic system ,Rheumatology ,Internal medicine ,medicine ,Animals ,Orthopedics and Sports Medicine ,Orchiectomy ,Angiopoietin-Like Protein 7 ,Estradiol ,Temporomandibular Joint ,business.industry ,Mandibular Condyle ,Calcinosis ,Dihydrotestosterone ,medicine.disease ,Up-Regulation ,Temporomandibular joint ,Mice, Inbred C57BL ,Disease Models, Animal ,stomatognathic diseases ,medicine.anatomical_structure ,Endocrinology ,Female ,Stress, Mechanical ,business ,medicine.drug ,Calcification ,Hormone - Abstract
Summary Objective To observe and analyze the interaction between excessive mechanical stress (MS) and decreased sex hormones on Temporomandibular Joint Osteoarthritis (TMJ-OA), and to discover TMJ-OA disease susceptibility genes by molecular biological analysis to elucidate part of the mechanism of TMJ-OA onset. Design For experimental groups, orchiectomy (ORX) or ovariectomy (OVX) was performed on sexually mature 8-week-old mice. A metal plate was attached to the posterior surface of the maxillary incisors to apply excessive MS on mandibular condyles. Male mice were divided into control, ORX, MS, and ORX + MS groups, while female mice were divided into control, OVX, MS, and OVX + MS groups. Mandibular condyles were evaluated by histology and molecular biology. Results Histomorphometric analysis of the TMJ in ORX + MS and OVX + MS groups revealed the thinnest chondrocyte layers, highest modified Mankin scores, and significant increases in the number of osteoclasts. Gene expression analysis indicated upregulation of Angptl7 and Car1 genes in the mandibular condyles of mice subjected to the combined effects of excessive MS and reduced sex hormones. In vitro analysis suggested that cartilage-like cells overexpressing Angptl7 enhanced calcification, and osteoblast-like cells overexpression Car1 suppressed cell proliferation and calcification. Conclusions A severe TMJ-OA mouse model was successfully developed by applying excessive MS on the mandibular condyle of male and female mice with reduced sex hormones. Disease-susceptibility genes Angptl7 and Car1 were newly discovered in the experimental groups, suggesting their involvement in the onset mechanism of TMJ-OA.
- Published
- 2021
37. Novel 1,3,5-Triazinyl Aminobenzenesulfonamides Incorporating Aminoalcohol, Aminochalcone and Aminostilbene Structural Motifs as Potent Anti-VRE Agents, and Carbonic Anhydrases I, II, VII, IX, and XII Inhibitors
- Author
-
Eva Havránková, Vladimír Garaj, Šárka Mascaretti, Andrea Angeli, Zuzana Soldánová, Miroslav Kemka, Jozef Motyčka, Marie Brázdová, Jozef Csöllei, Josef Jampílek, and Claudiu T. Supuran
- Subjects
Carbonic Anhydrase I ,QH301-705.5 ,carbonic anhydrase ,chalcone ,Antineoplastic Agents ,Molecular Dynamics Simulation ,Carbonic Anhydrase II ,Catalysis ,Article ,Inorganic Chemistry ,Structure-Activity Relationship ,Neoplasms ,Humans ,Physical and Theoretical Chemistry ,Biology (General) ,Carbonic Anhydrase IX ,Carbonic Anhydrase Inhibitors ,Molecular Biology ,QD1-999 ,Spectroscopy ,Carbonic Anhydrases ,Sulfonamides ,Organic Chemistry ,General Medicine ,HCT116 Cells ,vancomycin-resistant enterococci ,inhibition ,Computer Science Applications ,Anti-Bacterial Agents ,benzenesulfonamide ,Molecular Docking Simulation ,stilbene ,Chemistry ,triazine - Abstract
A series of 1,3,5-triazinyl aminobenzenesulfonamides substituted by aminoalcohol, aminostilbene, and aminochalcone structural motifs was synthesized as potential human carbonic anhydrase (hCA) inhibitors. The compounds were evaluated on their inhibition of tumor-associated hCA IX and hCA XII, hCA VII isoenzyme present in the brain, and physiologically important hCA I and hCA II. While the test compounds had only a negligible effect on physiologically important isoenzymes, many of the studied compounds significantly affected the hCA IX isoenzyme. Several compounds showed activity against hCA XII; (E)-4-{2-[(4-[(2,3-dihydroxypropyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (31) and (E)-4-{2-[(4-[(4-hydroxyphenyl)amino]-6-[(4-styrylphenyl)amino]-1,3,5-triazin-2-yl)amino]ethyl}benzenesulfonamide (32) were the most effective inhibitors with KIs = 4.4 and 5.9 nM, respectively. In addition, the compounds were tested against vancomycin-resistant Enterococcus faecalis (VRE) isolates. (E)-4-[2-({4-[(4-cinnamoylphenyl)amino]-6-[(4-hydroxyphenyl)amino]-1,3,5-triazin-2-yl}amino)ethyl]benzenesulfonamide (21) (MIC = 26.33 µM) and derivative 32 (MIC range 13.80–55.20 µM) demonstrated the highest activity against all tested strains. The most active compounds were evaluated for their cytotoxicity against the Human Colorectal Tumor Cell Line (HCT116 p53 +/+). Only 4,4’-[(6-chloro-1,3,5-triazin-2,4-diyl)bis(iminomethylene)]dibenzenesulfonamide (7) and compound 32 demonstrated an IC50 of ca. 6.5 μM; otherwise, the other selected derivatives did not show toxicity at concentrations up to 50 µM. The molecular modeling and docking of active compounds into various hCA isoenzymes, including bacterial carbonic anhydrase, specifically α-CA present in VRE, was performed to try to outline a possible mechanism of selective anti-VRE activity.
- Published
- 2022
38. Carbonic Anhydrase Inhibition Activities of Schiff’s Bases Based on Quinazoline-Linked Benzenesulfonamide
- Author
-
Adel S. El-Azab, Alaa A.-M. Abdel-Aziz, Hazem A. Ghabbour, Silvia Bua, Alessio Nocentini, Hamad M. Alkahtani, Nawaf A. Alsaif, Mohamed H. M. Al-Agamy, and Claudiu T. Supuran
- Subjects
Carbonic Anhydrase I ,Molecular Structure ,Organic Chemistry ,Pharmaceutical Science ,Carbonic Anhydrase II ,quinazolinones ,sulfonamide ,schiff’s bases ,selectivity CA inhibitors ,Analytical Chemistry ,Isoenzymes ,Structure-Activity Relationship ,Chemistry (miscellaneous) ,Drug Discovery ,Quinazolines ,Humans ,Molecular Medicine ,Physical and Theoretical Chemistry ,Carbonic Anhydrase Inhibitors ,Carbonic Anhydrases - Abstract
Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff’s bases based on quinazoline scaffold 4–27. The hCA I isoform was efficiently inhibited by Schiff’s bases 4–6, 10–19, 22–27 and had an inhibition constant (Ki) value of 52.8–991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8–52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2–27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5–99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15–19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4–25.5 nM vs. 5.7 nM of AAZ. Schiff’s bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46–107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04–58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7–14, 19–23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02–19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84–26.60 balanced to AAZ (SI, 0.48 and 2.10).
- Published
- 2022
- Full Text
- View/download PDF
39. Overexpression of CA1 mRNA and the CA I Protein in Tumor Cells Does Not Change the Gene Expression of the ECM Proteins
- Author
-
Ján Lakota and Mária Dubrovčáková
- Subjects
carbonic anhydrase i ,ca1 gene overexpression ,tumor cell ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
In our study, we performed retroviral transduction to overexpress codon-optimized variant of gene encoding human carbonic anhydrase I (optiCA1) in two tumor cell lines PC3 and MDA-MB-231, derived from human prostatic and breast carcinoma respectively. We achieved significantly enhanced and stable overexpression of exogenous optiCA1 gene. The expression of endogenous, wild CA1 gene was found to be normally low (Ct 28.6 for PC3 cells) or below to the detection limit (Ct 35.5 for MDA-MB-231 cells). No morphological changes and no decreasing viability of tumor cells were observed upon stable overexpression of the optiCA1 gene. In our study we have shown that the overexpression of the optimized human CA1 in engineered PC3 and MDA-MB-231 cells did not induce similar changes as we observed in tumor cells cultivated in the presence of human sera containing extensively high titers of anti-CA I autoantibodies from patients with complete remission of malignant disease. In both optiCA1transduced cell lines, the expression of selected genes responsible for basal lamina assembly, cytoskeleton, extracellular matrix proteins and proto-oncogenes (COL1A1, COL4A4, LAMC2, CTHRC1, and WNT7B) was not changed.
- Published
- 2020
- Full Text
- View/download PDF
40. Tip60 might be a candidate for the acetylation of hepatic carbonic anhydrase I and III in mice
- Author
-
Harun Budak, Nurdan Gonul Baltaci, and Enver Fehim Kocpinar
- Subjects
Circadian rhythm ,Bicarbonate ,Mutant ,Acetylation ,General Medicine ,Carbonic anhydrases ,Molecular biology ,Mice ,chemistry.chemical_compound ,Tip60 ,chemistry ,Knockout mouse ,Genetics ,Zeitgeber ,Carbonic Anhydrase I ,Molecular Biology ,Gene ,Southern blot - Abstract
Carbonic anhydrases (CAs) play an important role in maintaining pH balance by catalyzing the conversion of carbon dioxide to bicarbonate. Since this pH balance is critical to health, all organisms must develop mechanisms to control and regulate it. Although there is a great deal of literature on the biochemical, functional, and structural properties of the CA family, there is no enough knowledge on the regulation of CAs at gene and protein levels, especially their epigenetic regulation. In this study, impact of Tip60, a member of histone acetyltransferases family, on the expression of Ca1 and Ca3 genes in liver tissue was investigated at different zeitgeber time points in control and liver-specific Tip60 knockout mice (mutant) groups. First of all, Tip60 was specifically knocked out in mouse liver the using Cre/loxP system and knockout rate was shown as 83% - 88% by southern blot. Expression profiles of Ca1 and Ca3 genes in both groups were determined by Real-Time PCR at six different time points. While Ca1 showed the highest expression at ZT8 and ZT12, the lowest expression profile was observed at ZT0 and ZT20. Hepatic Ca1 showed a robust circadian expression. While hepatic Ca3 showed almost the same level of expression at different time units. The expression of Ca1 and Ca3 significantly decreased in the absence of Tip60 in mouse liver all time period. In conclusion, it was suggested for the first time that Tip60 may be considered a candidate protein in the regulation of Ca1 and Ca3 genes, possibly by acetylation.
- Published
- 2021
41. Repurposing of World-Approved Drugs for Potential Inhibition against Human Carbonic Anhydrase I: A Computational Study.
- Author
-
Zheng N, Jiang W, Zhang P, Ma L, Chen J, and Zhang H
- Subjects
- Humans, Drug Repositioning, Molecular Docking Simulation, Sulfanilamide, Sulfonamides pharmacology, Carbonic Anhydrase I, Carbonic Anhydrases
- Abstract
Human carbonic anhydrases (hCAs) have enzymatic activities for reversible hydration of CO
2 and are acknowledged as promising targets for the treatment of various diseases. Using molecular docking and molecular dynamics simulation approaches, we hit three compounds of methyl 4-chloranyl-2-(phenylsulfonyl)-5-sulfamoyl-benzoate (84Z for short), cyclothiazide, and 2,3,5,6-tetrafluoro-4-piperidin-1-ylbenzenesulfonamide (3UG for short) from the existing hCA I inhibitors and word-approved drugs. As a Zn2+ -dependent metallo-enzyme, the influence of Zn2+ ion models on the stability of metal-binding sites during MD simulations was addressed as well. MM-PBSA analysis predicted a strong binding affinity of -18, -16, and -14 kcal/mol, respectively, for these compounds, and identified key protein residues for binding. The sulfonamide moiety bound to the Zn2+ ion appeared as an essential component of hCA I inhibitors. Vina software predicted a relatively large (unreasonable) Zn2+ -sulfonamide distance, although the relative binding strength was reproduced with good accuracy. The selected compounds displayed potent inhibition against other hCA isoforms of II, XIII, and XIV. This work is valuable for molecular modeling of hCAs and further design of potent inhibitors.- Published
- 2023
- Full Text
- View/download PDF
42. Oral administration of human carbonic anhydrase I suppresses colitis in a murine inflammatory bowel disease model
- Author
-
Kazuhiro, Tange, Sen, Yagi, Eiji, Takeshita, Masanori, Abe, Yasunori, Yamamoto, Hideomi, Tomida, Tomoe, Kawamura, Masakazu, Hanayama, Bunzo, Matsuura, Yoshiou, Ikeda, and Yoichi, Hiasa
- Subjects
Carbonic Anhydrase I ,Multidisciplinary ,Interleukin-6 ,Prednisolone ,Interleukin-17 ,Administration, Oral ,Tretinoin ,Mice, SCID ,Nuclear Receptor Subfamily 1, Group F, Member 3 ,Colitis ,Inflammatory Bowel Diseases ,Phosphates ,Mice ,Interferon-gamma ,Disease Models, Animal ,Humans ,Animals ,Mesalamine - Abstract
The incidence of inflammatory bowel disease (IBD) is increasing; hence, effective treatments are warranted. The therapeutic effect of human carbonic anhydrase I (hCA I) in IBD remains unknown. Therefore, we investigated whether oral tolerization to hCA I would induce antigen-specific protection from intestinal inflammation in vivo. Severe combined immunodeficient mice received hCA I, keyhole limpet hemocyanin (KLH), or phosphate-buffered saline (PBS) orally for 7 days. Colons and mesenteric lymph nodes (MLNs) were collected 4 weeks after cell transfer. Additionally, the mechanisms underlying the therapeutic effects were investigated. The comparison between the effects of well-established drugs and hCA I oral administration was investigated. Oral administration of hCA I ameliorated colitis remarkably. hCA I reached the cecum and ameliorated colitis more effectively than mesalazine and similarly to prednisolone. Compared with PBS treatment, hCA I treatment reduced interleukin (IL)-17a, IL-6, and retinoic acid-related orphan receptor gamma t (RORγt) expression in the colon or MLNs; moreover, hCA I markedly reduced IL-6, IL-17, and interferon-gamma (IFN-γ) levels in the MLN. Oral administration of hCA I induced immune tolerance and suppressed colitis in vivo. Thus, hCA I administration could be proposed as a new treatment option for IBD.
- Published
- 2022
43. Silencing of CA1 mRNA in tumour cells does not change the gene expression of the extracellular matrix proteins.
- Author
-
Vulic, Radivojka, Tyciakova, Silvia, Dubrovcakova, Maria, Skultety, Ludovit, and Lakota, Jan
- Subjects
GENE silencing ,CARBONIC anhydrase ,MESSENGER RNA ,CANCER cells ,GENE expression ,EXTRACELLULAR matrix proteins - Abstract
We report the silencing of CA1 mRNA in PC3 and MDA cells. The levels of mRNA coding CA1 protein in the knock-down mRNA (CA1 siRNA) cells have been measured by RT-PCR and were approximately 5% (PC3) and 20% (MDA-MB-231), respectively, of the level of control (Mock siRNA) used during silencing. In PC3 and MDA-MB-231 cells, the mRNAs for COL1A1 and COL4A4 were up-regulated. The mRNAs for CTHRC1, LAMC2, and WNT7B were not changed when compared to the control. The morphology of the cells during the treatments remained the same. On the Western blots, the lysate from the silenced cells showed lower levels of CA I as well. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
44. Synthesis and biological evaluation of new pyrazolebenzene-sulphonamides as potential anticancer agents and hCA I and II inhibitors
- Author
-
Mehtap Tugrak, Ruya Kaya, Halise Inci Gul, Hiroshi Sakagami, İlhami Gülçin, and Belirlenecek
- Subjects
Chalcone ,Design ,Qsar ,carbonic anhydrase ,chalcone ,Apoptosis ,Pyrazoline ,Sulphonamide ,Carbonic-Anhydrase Inhibitors ,Chalcone Derivatives ,Bioactivity ,Article ,chemistry.chemical_compound ,Carbonic anhydrase ,Cytotoxic T cell ,Potency ,Carbonic Anhydrase I ,pyrazoline ,Cytotoxicity ,biology ,Bacterial ,General Chemistry ,Combinatorial chemistry ,chemistry ,biology.protein ,cytotoxicity ,Patent ,Sulfamides ,OSCC ,Selectivity - Abstract
Cancer is a disease characterized by the continuous growth of cells without adherence to the rules that healthy normal cells obey. Carbonic anhydrase I and II (CA I and CA II) inhibitors are used for the treatment of some diseases. The available drugs in the market have limitations or side effects, which bring about the need to develop new drug candidate compound(s) to overcome the problems at issue. In this study, new pyrazole-sulphonamide hybrid compounds 4-[5-(1,3-benzodioxol-5-yl)-3-aryl-4,5-dihydro-1H-pyrazol-1-yl]benzenesulphonamides (4a - 4j) were designed to discover new drug candidate compounds. The compounds 4a - 4j were synthesized and their chemical structures were confirmed using spectral techniques. The hypothesis tested was whether an introduction of methoxy and polymethoxy group(s) lead to an increased potency selectivity expression (PSE) value of the compound, which reflects cytotoxicity and selectivity of the compounds. The cytotoxicity of the compounds towards tumor cell lines were in the range of 6.7 - 400 mu M. The compounds 4i (PSE2 = 461.5) and 4g (PSE1 = 193.2) had the highest PSE values in cytotoxicity assays. Ki values of the compounds were in the range of 59.8 +/- 3.0 - 12.7 +/- 1.7 nM towards hCA I and in the range of 24.1 +/- 7.1 - 6.9 +/- 1.5 nM towards hCA II. While the compounds 4b, 4f, 4g, and 4i showed promising cytotoxic effects, the compounds 4c and 4g had the inhibitory potency towards hCA I and hCA II, respectively. These compounds can be considered as lead compounds for further research.
- Published
- 2021
45. Microwave assisted solvent-free mannich bases: synthesis, characterization and effects of these compounds on HCA I and HCA II isozymes
- Author
-
Nurgün Büyükkıdan, Evren Derrun Arslanbay, Melek Yılmaz, Metin Bülbül, Ekrem Tunca, Bülent Büyükkıdan, Büyükkıdan, Bülent, Büyükkıdan, Nurgün, Bülbül, Metin, Yılmaz, Melek, Arslanbey, Evren Derrun, and Tunca, Ekrem
- Subjects
biology ,Chemistry ,Activator (genetics) ,Stereochemistry ,General Chemical Engineering ,Glaucoma ,General Chemistry ,QD415-436 ,Isozyme ,Esterase ,Microwave assisted ,Biochemistry ,In vitro ,activator, carbonic anhydrase, glaucoma, isozyme ,Carbonic Anhydrase ,Chemical engineering ,Carbonic anhydrase ,medicine ,biology.protein ,Activator ,TP155-156 ,Carbonic Anhydrase I ,Acetazolamide ,medicine.drug - Abstract
Mannich bases (2a–d) of aromatic amines were synthesized by using a conventional microwave technique under solvent-free conditions and characterized by IR and NMR (1H and 13C) and elemental analysis. The inhibitory effects of the synthesized Mannich bases were examined in vitro by using hydratase and esterase assays on carbonic anhydrase I and II isozymes (hCA, EC 4.2.1.1) purified from human erythrocyte cells. Acetazolamide was used as the control compound. The values of IC50, the half-maximum inhibitory concentration, were found for hydratase and esterase activities. Only two compounds (2b and 2d) exhibited poor hCA I and hCA II inhibition effects on esterase activity. In contrast, compounds 2a and 2c could be used as carbonic anhydrase activators as a result of the increased esterase activity of hCA I and hCA II isozymes. © 2021, Macedonian Journal of Chemistry and Chemical Engineering. All Rights Reserved.
- Published
- 2021
46. New PEPPSI-Pd-NHC complexes bearing 4-hydroxyphenylethyl group: Synthesis, characterization, molecular docking, and bioactivity properties
- Author
-
Ayten Behçet, Parham Taslimi, Yetkin Gök, Aydın Aktaş, Tugba Taskin‐Tok, and İlhami Gülçin
- Subjects
Molecular Docking Simulation ,Structure-Activity Relationship ,Carbonic Anhydrase I ,Molecular Structure ,Pyridines ,Butyrylcholinesterase ,Drug Discovery ,Acetylcholinesterase ,Pharmaceutical Science ,Humans ,alpha-Glucosidases ,Cholinesterase Inhibitors ,Carbonic Anhydrase Inhibitors - Abstract
Five 4-hydroxyphenylethyl substituted pyridine enhanced, precatalyst, preparation, stabilization, and initiation-Pd-N-heterocyclic carbene (PEPPSI-Pd-NHC) complexes are synthesized in a straightforward way. All PEPPSI-Pd-NHC complexes were prepared by mixing 4-hydroxyphenylethyl substituted NHC precursors, palladium chloride, potassium carbonate, and potassium bromide in pyridine. All complexes were screened for human carbonic anhydrase I (hCA I) and hCA II, acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and α-glucosidase (α-Glu) inhibitory activities. The ChE inhibitory activities of the new PEPPSI-Pd-NHC complexes bearing the 4-hydroxyphenylethyl group (1a-e) against α-Glu, AChE, and BChE were determined by the Tao and Ellman methods. The results indicated that all the synthetic complexes exhibited potent inhibitory activities against all targets as compared to the standard inhibitors, revealed by IC
- Published
- 2022
47. Carbonic Anhydrase inhibitors bearing organotelluride moieties as novel agents for antitumor therapy
- Author
-
Andrea Petreni, Alexandra Iacobescu, Natalia Simionescu, Anca-Roxana Petrovici, Andrea Angeli, Adrian Fifere, Mariana Pinteala, and Claudiu T. Supuran
- Subjects
Pharmacology ,Carbonic Anhydrase I ,Organic Chemistry ,Antineoplastic Agents ,General Medicine ,Carbonic Anhydrase II ,Structure-Activity Relationship ,Antigens, Neoplasm ,Neoplasms ,Drug Discovery ,Tumor Microenvironment ,Humans ,Carbonic Anhydrase Inhibitors ,Reactive Oxygen Species ,Carbonic Anhydrase IX ,Carbonic Anhydrases - Abstract
Solid tumors are mainly characterized by a specific hypoxic microenvironment which makes them particularly challenging to treat. The Carbonic Anhydrase IX (CA IX) is one of the major enzymes implicated in the regulation and maintaining of such conditions and therefore its targeting represents a winning approach in recent tumor targeted therapy. In our search for an innovative combination therapy, we attained the synthesis of selective CA IX inhibitors which are also used for cell specific delivery of cytotoxic organotellurium scaffolds. We investigated compounds 5b, 7b and 7c for their redox properties by means of radical species scavenging and lipid peroxidation inhibitory capacity, as well as intracellular (reactive oxygen species) ROS production in both normal and cancer cell lines. Subsequently, compounds were evaluated as possible free radical generators by ESR spectrometry showing to cause or promote the formation of free radicals. These results accounted for a novel, potent, and selective CA IX inhibitor (i.e. 7c, K
- Published
- 2022
48. Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII
- Author
-
Arzu Gumus, Murat Bozdag, Atilla Akdemir, Andrea Angeli, Silvia Selleri, Fabrizio Carta, Claudiu T. Supuran, and AKDEMİR, ATİLLA
- Subjects
Carbonic Anhydrase I ,carbonic anhydrase inhibitors ,privileged scaffolds ,coumarins ,thiosemicarbazides ,Molecular Structure ,Organic Chemistry ,Pharmaceutical Science ,GÜMÜŞ PALABIYIK A., Bozdag M., AKDEMİR A., Angeli A., Selleri S., Carta F., Supuran C. T. , -Thiosemicarbazide-Substituted Coumarins as Selective Inhibitors of the Tumor Associated Human Carbonic Anhydrases IX and XII-, MOLECULES, cilt.27, sa.14, 2022 ,Analytical Chemistry ,Semicarbazides ,Structure-Activity Relationship ,Chemistry (miscellaneous) ,Antigens, Neoplasm ,Coumarins ,Neoplasms ,Drug Discovery ,Molecular Medicine ,Humans ,Physical and Theoretical Chemistry ,Carbonic Anhydrase IX ,Carbonic Anhydrase Inhibitors ,Carbonic Anhydrases - Abstract
A novel series of thiosemicarbazide-substituted coumarins was synthesized and the inhibitory effects against four physiologically relevant carbonic anhydrase isoforms I, II, IX and XII showed selective activities on the tumor-associated IX and XII isozymes. Molecular modeling studies on selected compounds 14a and 22a were performed. The binding modes of such compounds were determined assuming their enzymatically active structures (i.e., cinnamic acid) in the thermodynamically favored, and not previously explored, E geometry. Molecular modelling suggests multiple interactions within the enzymatic cavity and may explain the high potency and selectivity reported for the hCAs IX and XII.
- Published
- 2022
49. Discovery of Potent Carbonic Anhydrase Inhibitors as Effective Anticonvulsant Agents: Drug Design, Synthesis, and In Vitro and In Vivo Investigations
- Author
-
Manisha Tiwari, Silvia Bua, Chandra Bhushan Mishra, Raj Kumar Mongre, Claudiu T. Supuran, Andrea Angeli, and Shikha Kumari
- Subjects
Male ,Carbonic Anhydrase I ,medicine.medical_treatment ,Pharmacology ,Carbonic Anhydrase II ,01 natural sciences ,03 medical and health sciences ,Epilepsy ,In vivo ,Carbonic anhydrase ,Drug Discovery ,medicine ,Animals ,Humans ,Rats, Wistar ,Carbonic Anhydrase Inhibitors ,Carbonic Anhydrases ,030304 developmental biology ,0303 health sciences ,biology ,Chemistry ,Drug discovery ,medicine.disease ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,Anticonvulsant Agent ,Anticonvulsant ,Cell culture ,Drug Design ,biology.protein ,Molecular Medicine ,Anticonvulsants - Abstract
Two sets of benzenesulfonamide-based effective human carbonic anhydrase (hCA) inhibitors have been developed using the tail approach. The inhibitory action of these novel molecules was examined against four isoforms: hCA I, hCA II, hCA VII, and hCA XII. Most of the molecules disclosed low to medium nanomolar range inhibition against all tested isoforms. Some of the synthesized derivatives selectively inhibited the epilepsy-involved isoforms hCA II and hCA VII, showing low nanomolar affinity. The anticonvulsant activity of selected sulfonamides was assessed using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) in vivo models of epilepsy. These potent CA inhibitors effectively inhibited seizures in both epilepsy models. The most effective compounds showed long duration of action and abolished MES-induced seizures up to 6 h after drug administration. These sulfonamides were found to be orally active anticonvulsants, being nontoxic in neuronal cell lines and in animal models.
- Published
- 2021
50. Molecular cloning and transcriptional regulation of two γ-carbonic anhydrase genes in the green macroalga Ulva prolifera
- Author
-
Feng Liu, Yu Wang, Yuping Bi, Shitao Shi, Manman Liu, and Nansheng Chen
- Subjects
0106 biological sciences ,0301 basic medicine ,China ,Carbonic Anhydrase I ,Transcription, Genetic ,Plant Science ,Chlorophyta ,Carbonic Anhydrase II ,010603 evolutionary biology ,01 natural sciences ,Ulva ,03 medical and health sciences ,Transcription (biology) ,Carbonic anhydrase ,Genetics ,Transcriptional regulation ,Cloning, Molecular ,Gene ,Phylogeny ,Histidine ,biology ,Ulvophyceae ,Ulva prolifera ,General Medicine ,biology.organism_classification ,030104 developmental biology ,Gene Expression Regulation ,Biochemistry ,Insect Science ,biology.protein ,Animal Science and Zoology - Abstract
Ulva prolifera O.F. Müller (Ulvophyceae, Chlorophyta) is well known as a typical green-tide forming macroalga which has caused the world's largest macroalgal blooms in the Yellow Sea of China. In this study, two full-length γ-carbonic anhydrase (γ-CA) genes (UpγCA1 and UpγCA2) were cloned from U. prolifera. UpγCA1 has three conserved histidine residues, which act as an active site for binding a zinc metal ion. In UpγCA2, two of the three histidine residues were replaced by serine and arginine, respectively. The two γ-CA genes are clustered together with other γ-CAs in Chlorophyta with strong support value (100% bootstrap) in maximum likelihood (ML) phylogenetic tree. Quantitative real-time PCR (qRT-PCR) analysis showed that stressful environmental conditions markedly inhibited transcription levels of these two γ-CA genes. Low pH value (pH 7.5) significantly increased transcription level of UpγCA2 not UpγCA1 at 12 h, whereas high pH value (pH 8.5) significantly inhibited the transcription of these two γ-CA genes at 6 h. These findings enhanced our understanding on transcriptional regulation of γ-CA genes in response to environmental factors in U. prolifera.
- Published
- 2021
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.