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Carbonic Anhydrase and Carbonic Anhydrase Inhibitors

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 48408

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Collection Editor
Neurofarba Department, Section of Farmaceutical and Neutraceutical Sciences, University of Florence, Sesto Fiorentino, 50019 Florence, Italy
Interests: drug design; metalloenzymes; carbonic anhydrases; anticancer agents; antiinfectives; sulfonamides; coumarins
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Dear Colleagues,

The metalloenzyme carbonic anhydrase (CA) is expressed in organisms all over the phylogenetic tree of life, with eight genetic families known to date. By equilibrating CO2 and bicarbonate with the generation of protons, CAs play a crucial role in pH regulation, electrolyte secretion, metabolism (lipogenesis, gluconeogenesis, ureagenesis). CA inhibitors are clinically used as diuretics, antiglaucoma agents, and antiepileptics, but novel applications in the management of cancer, neuropathic pain, sleep apnea, migraine, intracranial pressure lowering, and cerebral ischemia are being investigated. CA activators are involved in memory and fear extinction, and are thus useful in the treatment of cognitive impairment and phobias. This topical collection provides an update in these fields, with reviews/original articles dedicated to the various applications of inhibitors/activators in therapy as well as biomedical applications of prokaryotic CAs, with CAs widely abundant in pathogenic bacteria in addition to fungi, protozoa, and other pathogens. The modulators of activity of these enzymes offer useful applications in a variety of biomedical and biotechnological fields.

Prof. Dr. Claudiu T. Supuran
Collection Editor

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Keywords

  • Carbonic anhydrase
  • Inhibitor
  • Activator
  • Antitumor agent
  • Anti-infectives
  • Diuretics
  • Antiepileptics
  • Alzheimer’s disease

Published Papers (17 papers)

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20 pages, 4679 KiB  
Article
Synthesis, Biological and In Silico Studies of Griseofulvin and Usnic Acid Sulfonamide Derivatives as Fungal, Bacterial and Human Carbonic Anhydrase Inhibitors
by Andrea Angeli, Anthi Petrou, Victor Kartsev, Boris Lichitsky, Andrey Komogortsev, Clemente Capasso, Athina Geronikaki and Claudiu T. Supuran
Int. J. Mol. Sci. 2023, 24(3), 2802; https://doi.org/10.3390/ijms24032802 - 01 Feb 2023
Cited by 4 | Viewed by 1611
Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of griseofulvin and usnic acid sulfonamides were synthesized and tested as possible [...] Read more.
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho-/physiological conditions. A series of griseofulvin and usnic acid sulfonamides were synthesized and tested as possible CA inhibitors. Since β- and γ- classes are expressed in microorganisms in addition to the α- class, showing substantial structural differences to the human isoforms they are also interesting as new antiinfective targets with a different mechanism of action for fighting the emerging problem of extensive drug resistance afflicting most countries worldwide. Griseofulvin and usnic acid sulfonamides were synthesized using methods of organic chemistry. Their inhibitory activity, assessed against the cytosolic human isoforms hCA I and hCA II, the transmembrane hCA IX as well as β- and γ-CAs from different bacterial and fungal strains, was evaluated by a stopped-flow CO2 hydrase assay. Several of the investigated derivatives showed interesting inhibition activity towards the cytosolic associate isoforms hCA I and hCA II, as well as the three γ-CAs and Malassezia globosa (MgCA) enzyme. Six compounds (1b1d, 1h, 1i and 1j) were more potent than AAZ against hCA I while five (1d, 1h, 1i, 1j and 4a) showed better activity than AAZ against the hCA II isoform. Moreover, all compounds appeared to be very potent against MgCA with a Ki lower than that of the reference drug. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds within the active site of human CAs. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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26 pages, 7487 KiB  
Article
Novel Insights on Human Carbonic Anhydrase Inhibitors Based on Coumalic Acid: Design, Synthesis, Molecular Modeling Investigation, and Biological Studies
by Virginia Pontecorvi, Mattia Mori, Francesca Picarazzi, Susi Zara, Simone Carradori, Amelia Cataldi, Andrea Angeli, Emanuela Berrino, Paola Chimenti, Alessia Ciogli, Daniela Secci, Paolo Guglielmi and Claudiu T. Supuran
Int. J. Mol. Sci. 2022, 23(14), 7950; https://doi.org/10.3390/ijms23147950 - 19 Jul 2022
Cited by 10 | Viewed by 1716
Abstract
Human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII are overexpressed in solid hypoxic tumors, and they are considered as prognostic tools and therapeutic targets for cancer. Based on a molecular simplification of the well-known coumarin scaffold, we developed a new series [...] Read more.
Human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms IX and XII are overexpressed in solid hypoxic tumors, and they are considered as prognostic tools and therapeutic targets for cancer. Based on a molecular simplification of the well-known coumarin scaffold, we developed a new series of derivatives of the pyran-2-one core. The new compounds are endowed with potent and selective inhibitory activity against the tumor-related hCA isoforms IX and XII, in the low nanomolar range, whereas they are inactive against the two cytosolic off-targets hCA I and II. The compounds exhibiting the best hCA inhibition were further investigated against the breast adenocarcinoma cell line (MCF7) in hypoxic conditions, evaluating their ability to eventually synergize with doxorubicin. The compounds’ biocompatibility on healthy cells was also tested and confirmed on Human Gingival Fibroblasts (HGFs). Furthermore, the possible binding mode of all compounds to the active site of the tumor-associated human CA IX was investigated by computational techniques which predicted the binding conformations and the persistency of binding poses within the active site of the enzyme, furnishing relevant data for the design of tight binding inhibitors. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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24 pages, 6831 KiB  
Article
Squaramide-Tethered Sulfonamides and Coumarins: Synthesis, Inhibition of Tumor-Associated CAs IX and XII and Docking Simulations
by Giulia Arrighi, Adrián Puerta, Andrea Petrini, Francisco J. Hicke, Alessio Nocentini, Miguel X. Fernandes, José M. Padrón, Claudiu T. Supuran, José G. Fernández-Bolaños and Óscar López
Int. J. Mol. Sci. 2022, 23(14), 7685; https://doi.org/10.3390/ijms23147685 - 12 Jul 2022
Cited by 9 | Viewed by 2492
Abstract
(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a [...] Read more.
(1) Background: carbonic anhydrases (CAs) are attractive targets for the development of new anticancer therapies; in particular, CAs IX and XII isoforms are overexpressed in numerous tumors. (2) Methods: following the tail approach, we have appended a hydrophobic aromatic tail to a pharmacophore responsible for the CA inhibition (aryl sulfonamide, coumarin). As a linker, we have used squaramides, featured with strong hydrogen bond acceptor and donor capacities. (3) Results: Starting from easily accessible dimethyl squarate, the title compounds were successfully obtained as crystalline solids, avoiding the use of chromatographic purifications. Interesting and valuable SARs could be obtained upon modification of the length of the hydrocarbon chain, position of the sulfonamido moiety, distance of the aryl sulfonamide scaffold to the squaramide, stereoelectronic effects on the aromatic ring, as well as the number and type of substituents on C-3 and C-4 positions of the coumarin. (4) Conclusions: For sulfonamides, the best profile was achieved for the m-substituted derivative 11 (Ki = 29.4, 9.15 nM, CA IX and XII, respectively), with improved selectivity compared to acetazolamide, a standard drug. Coumarin derivatives afforded an outstanding selectivity (Ki > 10,000 nM for CA I, II); the lead compound (16c) was a strong CA IX and XII inhibitor (Ki = 19.2, 7.23 nM, respectively). Docking simulations revealed the key ligand-enzyme interactions. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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15 pages, 6916 KiB  
Article
Identification of Novel and Potent Indole-Based Benzenesulfonamides as Selective Human Carbonic Anhydrase II Inhibitors: Design, Synthesis, In Vitro, and In Silico Studies
by Ahmed Elkamhawy, Jiyu Woo, Hossam Nada, Andrea Angeli, Tarek M. Bedair, Claudiu T. Supuran and Kyeong Lee
Int. J. Mol. Sci. 2022, 23(5), 2540; https://doi.org/10.3390/ijms23052540 - 25 Feb 2022
Cited by 9 | Viewed by 2416
Abstract
In recent decades, human carbonic anhydrase inhibitors (hCAIs) have emerged as an important therapeutic class with various applications including antiglaucoma, anticonvulsants, and anticancer agents. Herein, a novel series of indole-based benzenesulfonamides were designed, synthesized, and biologically evaluated as potential hCAIs. A regioisomerism of [...] Read more.
In recent decades, human carbonic anhydrase inhibitors (hCAIs) have emerged as an important therapeutic class with various applications including antiglaucoma, anticonvulsants, and anticancer agents. Herein, a novel series of indole-based benzenesulfonamides were designed, synthesized, and biologically evaluated as potential hCAIs. A regioisomerism of the sulfonamide moiety was carried out to afford a total of fifteen indole-based benzenesulfonamides possessing different amide linkers that enable the ligands to be flexible and develop potential H-bond interaction(s) with the target protein. The activity of the synthesized compounds was evaluated against four hCA isoforms (I, II, IX and, XII). Compounds 2b, 2c, 2d, 2f, 2h and 2o exhibited potent and selective profiles over the hCA II isoform with Ki values of 7.3, 9.0, 7.1, 16.0, 8.6 and 7.5 nM, respectively. Among all, compound 2a demonstrated the most potent inhibition against the hCA II isoform with an inhibitory constant (Ki) of 5.9 nM, with 13-, 34-, and 9-fold selectivity for hCA II over I, IX and XII isoforms, respectively. Structure–activity relationship data attained for various substitutions were rationalized. Furthermore, a molecular docking study gave insights into both inhibitory activity and selectivity of the target compounds. Accordingly, this report presents a successful scaffold hoping approach that reveals compound 2a as a highly potent and selective indole-based hCA II inhibitor worthy of further investigation. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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45 pages, 11117 KiB  
Article
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
by Eva Havránková, Vladimír Garaj, Šárka Mascaretti, Andrea Angeli, Zuzana Soldánová, Miroslav Kemka, Jozef Motyčka, Marie Brázdová, Jozef Csöllei, Josef Jampílek and Claudiu T. Supuran
Int. J. Mol. Sci. 2022, 23(1), 231; https://doi.org/10.3390/ijms23010231 - 26 Dec 2021
Cited by 7 | Viewed by 3806
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, [...] Read more.
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. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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20 pages, 9777 KiB  
Article
Inhibition of Carbonic Anhydrase 2 Overcomes Temozolomide Resistance in Glioblastoma Cells
by Kai Zhao, Agnes Schäfer, Zhuo Zhang, Katharina Elsässer, Carsten Culmsee, Li Zhong, Axel Pagenstecher, Christopher Nimsky and Jörg W. Bartsch
Int. J. Mol. Sci. 2022, 23(1), 157; https://doi.org/10.3390/ijms23010157 - 23 Dec 2021
Cited by 11 | Viewed by 3365
Abstract
About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resistant glioblastoma stem-like cells (GSCs). Here [...] Read more.
About 95% of Glioblastoma (GBM) patients experience tumor relapse as a consequence of resistance to the first-line standard chemotherapy using temozolomide (TMZ). Recent studies reported consistently elevated expression levels of carbonic anhydrase CA2 in recurrent glioblastoma and temozolomide-resistant glioblastoma stem-like cells (GSCs). Here we show that CA2 is preferentially expressed in GSCs and upregulated by TMZ treatment. When expressed in GBM cell lines, CA2 exerts significant metabolic changes reflected by enhanced oxygen consumption and increased extracellular acidification causing higher rates of cell invasion. Notably, GBM cells expressing CA2 respond to combined treatment with TMZ and brinzolamide (BRZ), a non-toxic and potent CA2 inhibitor. Interestingly, brinzolamide was more effective than the pan-CA inhibitor Acetazolamide (ACZ) to sensitize naïve GSCs and TMZ-resistant GSCs to TMZ induced cell death. Mechanistically, we demonstrated that the combined treatment of GBM stem cells with TMZ and BRZ caused autophagy of GBM cell lines and GSCs, reflected by enhanced LC3 cleavage (LC3-II) and p62 reduction. Our findings illustrate the potential of CA2 as a chemo-sensitizing drug target in recurrent GBM and propose a combined treatment of TMZ with CA2 inhibitor to tackle GBM chemoresistance and recurrence. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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19 pages, 2839 KiB  
Article
Synthesis, Molecular Docking Analysis, and Biological Evaluations of Saccharide-Modified Sulfonamides as Carbonic Anhydrase IX Inhibitors
by Zuopeng Zhang, Huali Yang, Ye Zhong, Yueqing Wang, Jian Wang, Maosheng Cheng and Yang Liu
Int. J. Mol. Sci. 2021, 22(24), 13610; https://doi.org/10.3390/ijms222413610 - 19 Dec 2021
Cited by 1 | Viewed by 2473
Abstract
Based on the strategy of the “tail approach”, 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds [...] Read more.
Based on the strategy of the “tail approach”, 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds showed good activity against CAs and high topological polar surface area (TPSA) values, which had a positive effect on the selective inhibition of transmembrane isoforms CA IX and XII. In the in vitro activity studies, compounds 16a, 16b, and 16e reduced the viability of HT-29 and MDA-MB-231 cells with a high expression of CA IX under hypoxia. The inhibitory activity of compound 16e on the human osteosarcoma cell line MG-63 with a high expression of CA IX and XII was better than that of AZM. Moreover, high concentrations of compounds 16a and 16b reversed the acidification of the tumour microenvironment. In addition, compound 16a had a certain inhibitory effect on the migration of MDA-MB-231 cells. All the above results indicate that the saccharide-modified sulfonamide has further research value for the development of CA IX inhibitors. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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19 pages, 3810 KiB  
Article
Synthesis and Inhibition Activity Study of Triazinyl-Substituted Amino(alkyl)-benzenesulfonamide Conjugates with Polar and Hydrophobic Amino Acids as Inhibitors of Human Carbonic Anhydrases I, II, IV, IX, and XII
by Mária Bodnár Mikulová, Dáša Kružlicová, Daniel Pecher, Andrea Petreni, Claudiu T. Supuran and Peter Mikuš
Int. J. Mol. Sci. 2021, 22(20), 11283; https://doi.org/10.3390/ijms222011283 - 19 Oct 2021
Cited by 1 | Viewed by 2113
Abstract
Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a [...] Read more.
Primary sulfonamide derivatives with various heterocycles represent the most widespread group of potential human carbonic anhydrase (hCA) inhibitors with high affinity and selectivity towards specific isozymes from the hCA family. In this work, new 4-aminomethyl- and aminoethyl-benzenesulfonamide derivatives with 1,3,5-triazine disubstituted with a pair of identical amino acids, possessing a polar (Ser, Thr, Asn, Gln) and non-polar (Ala, Tyr, Trp) side chain, have been synthesized. The optimized synthetic, purification, and isolation procedures provided several pronounced benefits such as a short reaction time (in sodium bicarbonate aqueous medium), satisfactory yields for the majority of new products (20.6–91.8%, average 60.4%), an effective, well defined semi-preparative RP-C18 liquid chromatography (LC) isolation of desired products with a high purity (>97%), as well as preservation of green chemistry principles. These newly synthesized conjugates, plus their 4-aminobenzenesulfonamide analogues prepared previously, have been investigated in in vitro inhibition studies towards hCA I, II, IV and tumor-associated isozymes IX and XII. The experimental results revealed the strongest inhibition of hCA XII with low nanomolar inhibitory constants (Kis) for the derivatives with amino acids possessing non-polar side chains (7.5–9.6 nM). Various derivatives were also promising for some other isozymes. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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22 pages, 34513 KiB  
Article
Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells
by Antje Güttler, Yvonne Eiselt, Anne Funtan, Andreas Thiel, Marina Petrenko, Jacqueline Keßler, Iris Thondorf, Reinhard Paschke, Dirk Vordermark and Matthias Bache
Int. J. Mol. Sci. 2021, 22(16), 8808; https://doi.org/10.3390/ijms22168808 - 16 Aug 2021
Cited by 14 | Viewed by 2692
Abstract
Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer [...] Read more.
Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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16 pages, 4501 KiB  
Article
Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells
by Ebru Temiz, Ismail Koyuncu, Mustafa Durgun, Murat Caglayan, Ataman Gonel, Eray Metin Güler, Abdurrahim Kocyigit and Claudiu T. Supuran
Int. J. Mol. Sci. 2021, 22(11), 6098; https://doi.org/10.3390/ijms22116098 - 05 Jun 2021
Cited by 22 | Viewed by 3167
Abstract
Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers [...] Read more.
Carbonic anhydrase IX (CAIX) is a hypoxia-related protein that plays a role in proliferation in solid tumours. However, how CAIX increases proliferation and metastasis in solid tumours is unclear. The objective of this study was to investigate how a synthetic CAIX inhibitor triggers apoptosis in the HeLa cell line. The intracellular effects of CAIX inhibition were determined with AO/EB, AnnexinV-PI, and γ-H2AX staining; measurements of intracellular pH (pHi), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP); and analyses of cell cycle, apoptotic, and autophagic modulator gene expression (Bax, Bcl-2, caspase-3, caspase-8, caspase-9, caspase-12, Beclin, and LC3), caspase protein level (pro-caspase 3 and cleaved caspase-3, -8, -9), cleaved PARP activation, and CAIX protein level. Sulphonamide CAIX inhibitor E showed the lowest IC50 and the highest selectivity index in CAIX-positive HeLa cells. CAIX inhibition changed the morphology of HeLa cells and increased the ratio of apoptotic cells, dramatically disturbing the homeostasis of intracellular pHi, MMP and ROS levels. All these phenomena consequent to CA IX inhibition triggered apoptosis and autophagy in HeLa cells. Taken together, these results further endorse the previous findings that CAIX inhibitors represent an important therapeutic strategy, which is worth pursuing in different cancer types, considering that presently only one sulphonamide inhibitor, SLC-0111, has arrived in Phase Ib/II clinical trials as an antitumour/antimetastatic drug. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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20 pages, 2605 KiB  
Article
Synthesis, Molecular Docking Analysis and Biological Evaluations of Saccharide-Modified Thiadiazole Sulfonamide Derivatives
by Zuo-Peng Zhang, Ye Zhong, Zhen-Bin Han, Lin Zhou, Hua-Sheng Su, Jian Wang, Yang Liu and Mao-Sheng Cheng
Int. J. Mol. Sci. 2021, 22(11), 5482; https://doi.org/10.3390/ijms22115482 - 22 May 2021
Cited by 5 | Viewed by 2471
Abstract
A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme [...] Read more.
A series of saccharide-modified thiadiazole sulfonamide derivatives has been designed and synthesized by the “tail approach” and evaluated for inhibitory activity against carbonic anhydrases II, IX, and XII. Most of the compounds showed high topological polar surface area (TPSA) values and excellent enzyme inhibitory activity. The impacts of some compounds on the viability of HT-29, MDA-MB-231, and MG-63 human cancer cell lines were examined under both normoxic and hypoxic conditions, and they showed certain inhibitory effects on cell viability. Moreover, it was found that the series of compounds had the ability to raise the pH of the tumor cell microenvironment. All the results proved that saccharide-modified thiadiazole sulfonamides have important research prospects for the development of CA IX inhibitors. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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15 pages, 1245 KiB  
Article
Chromene-Containing Aromatic Sulfonamides with Carbonic Anhydrase Inhibitory Properties
by Andrea Angeli, Victor Kartsev, Anthi Petrou, Mariana Pinteala, Volodymyr Brovarets, Sergii Slyvchuk, Stepan Pilyo, Athina Geronikaki and Claudiu T. Supuran
Int. J. Mol. Sci. 2021, 22(10), 5082; https://doi.org/10.3390/ijms22105082 - 11 May 2021
Cited by 6 | Viewed by 2261
Abstract
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their [...] Read more.
Carbonic anhydrases (CAs, EC 4.2.1.1) catalyze the essential reaction of CO2 hydration in all living organisms, being actively involved in the regulation of a plethora of patho/physiological conditions. A series of chromene-based sulfonamides were synthesized and tested as possible CA inhibitors. Their inhibitory activity was assessed against the cytosolic human isoforms hCA I, hCA II and the transmembrane hCA IX and XII. Several of the investigated derivatives showed interesting inhibition activity towards the tumor associate isoforms hCA IX and hCA XII. Furthermore, computational procedures were used to investigate the binding mode of this class of compounds, within the active site of hCA IX. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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Review

Jump to: Research

25 pages, 2584 KiB  
Review
Potential Novel Role of Membrane-Associated Carbonic Anhydrases in the Kidney
by Seong-Ki Lee, Walter F. Boron and Rossana Occhipinti
Int. J. Mol. Sci. 2023, 24(4), 4251; https://doi.org/10.3390/ijms24044251 - 20 Feb 2023
Cited by 3 | Viewed by 2593
Abstract
Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO2) and water into bicarbonate (HCO3) and protons (H+), thereby influencing pH, are near the core of virtually all physiological processes in the body. In [...] Read more.
Carbonic anhydrases (CAs), because they catalyze the interconversion of carbon dioxide (CO2) and water into bicarbonate (HCO3) and protons (H+), thereby influencing pH, are near the core of virtually all physiological processes in the body. In the kidneys, soluble and membrane-associated CAs and their synergy with acid–base transporters play important roles in urinary acid secretion, the largest component of which is the reabsorption of HCO3 in specific nephron segments. Among these transporters are the Na+-coupled HCO3 transporters (NCBTs) and the Cl-HCO3 exchangers (AEs)—members of the “solute-linked carrier” 4 (SLC4) family. All of these transporters have traditionally been regarded as “HCO3“ transporters. However, recently our group has demonstrated that two of the NCBTs carry CO32− rather than HCO3 and has hypothesized that all NCBTs follow suit. In this review, we examine current knowledge on the role of CAs and “HCO3” transporters of the SLC4 family in renal acid–base physiology and discuss how our recent findings impact renal acid secretion, including HCO3 reabsorption. Traditionally, investigators have associated CAs with producing or consuming solutes (CO2, HCO3, and H+) and thus ensuring their efficient transport across cell membranes. In the case of CO32− transport by NCBTs, however, we hypothesize that the role of membrane-associated CAs is not the appreciable production or consumption of substrates but the minimization of pH changes in nanodomains near the membrane. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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16 pages, 3810 KiB  
Review
α-CAs from Photosynthetic Organisms
by Emma Langella, Anna Di Fiore, Vincenzo Alterio, Simona Maria Monti, Giuseppina De Simone and Katia D’Ambrosio
Int. J. Mol. Sci. 2022, 23(19), 12045; https://doi.org/10.3390/ijms231912045 - 10 Oct 2022
Cited by 8 | Viewed by 2003
Abstract
Carbonic anhydrases (CAs) are ubiquitous enzymes that catalyze the reversible carbon dioxide hydration reaction. Among the eight different CA classes existing in nature, the α-class is the largest one being present in animals, bacteria, protozoa, fungi, and photosynthetic organisms. Although many studies have [...] Read more.
Carbonic anhydrases (CAs) are ubiquitous enzymes that catalyze the reversible carbon dioxide hydration reaction. Among the eight different CA classes existing in nature, the α-class is the largest one being present in animals, bacteria, protozoa, fungi, and photosynthetic organisms. Although many studies have been reported on these enzymes, few functional, biochemical, and structural data are currently available on α-CAs isolated from photosynthetic organisms. Here, we give an overview of the most recent literature on the topic. In higher plants, these enzymes are engaged in both supplying CO2 at the Rubisco and determining proton concentration in PSII membranes, while in algae and cyanobacteria they are involved in carbon-concentrating mechanism (CCM), photosynthetic reactions and in detecting or signaling changes in the CO2 level in the environment. Crystal structures are only available for three algal α-CAs, thus not allowing to associate specific structural features to cellular localizations or physiological roles. Therefore, further studies on α-CAs from photosynthetic organisms are strongly needed to provide insights into their structure–function relationship. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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22 pages, 4803 KiB  
Review
New Developments in Carbonic Anhydrase IX-Targeted Fluorescence and Nuclear Imaging Agents
by Kuo-Ting Chen and Yann Seimbille
Int. J. Mol. Sci. 2022, 23(11), 6125; https://doi.org/10.3390/ijms23116125 - 30 May 2022
Cited by 7 | Viewed by 3361
Abstract
Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular imaging of solid malignancies. The nuclear- and optical-imaging of CAIX-expressing tumors have received great attention due to their potential for clinical applications. Nuclear imaging is a powerful tool for the [...] Read more.
Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular imaging of solid malignancies. The nuclear- and optical-imaging of CAIX-expressing tumors have received great attention due to their potential for clinical applications. Nuclear imaging is a powerful tool for the non-invasive diagnosis of primary and metastatic CAIX-positive tumors and for the assessment of responses to antineoplastic treatment. Intraoperative optical fluorescence imaging provides improved visualization for surgeons to increase the discrimination of tumor lesions, allowing for safer surgical treatment. Over the past decades, many CAIX-targeted molecular imaging probes, based on monoclonal antibodies, antibody fragments, peptides, and small molecules, have been reported. In this review, we outline the recent development of CAIX-targeted probes for single-photon emission computerized tomography (SPECT), positron emission tomography (PET), and near-infrared fluorescence imaging (NIRF), and we discuss issues yet to be addressed. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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30 pages, 7529 KiB  
Review
Carbonic Anhydrase IX Inhibitors as Candidates for Combination Therapy of Solid Tumors
by Stanislav Kalinin, Anna Malkova, Tatiana Sharonova, Vladimir Sharoyko, Alexander Bunev, Claudiu T. Supuran and Mikhail Krasavin
Int. J. Mol. Sci. 2021, 22(24), 13405; https://doi.org/10.3390/ijms222413405 - 14 Dec 2021
Cited by 24 | Viewed by 4142
Abstract
Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant [...] Read more.
Combination therapy is becoming imperative for the treatment of many cancers, as it provides a higher chance of avoiding drug resistance and tumor recurrence. Among the resistance-conferring factors, the tumor microenvironment plays a major role, and therefore, represents a viable target for adjuvant therapeutic agents. Thus, hypoxia and extracellular acidosis are known to select for the most aggressive and resilient phenotypes and build poorly responsive regions of the tumor mass. Carbonic anhydrase (CA, EC 4.2.1.1) IX isoform is a surficial zinc metalloenzyme that is proven to play a central role in regulating intra and extracellular pH, as well as modulating invasion and metastasis processes. With its strong association and distribution in various tumor tissues and well-known druggability, this protein holds great promise as a target to pharmacologically interfere with the tumor microenvironment by using drug combination regimens. In the present review, we summarized recent publications revealing the potential of CA IX inhibitors to intensify cancer chemotherapy and overcome drug resistance in preclinical settings. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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10 pages, 1637 KiB  
Review
Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents
by Irene Bulli, Ilaria Dettori, Elisabetta Coppi, Federica Cherchi, Martina Venturini, Lorenzo Di Cesare Mannelli, Carla Ghelardini, Alessio Nocentini, Claudiu T. Supuran, Anna Maria Pugliese and Felicita Pedata
Int. J. Mol. Sci. 2021, 22(9), 5029; https://doi.org/10.3390/ijms22095029 - 10 May 2021
Cited by 11 | Viewed by 3515
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood [...] Read more.
Ischemic stroke is a leading cause of death and disability worldwide. The only pharmacological treatment available to date for cerebral ischemia is tissue plasminogen activator (t-PA) and the search for successful therapeutic strategies still remains a major challenge. The loss of cerebral blood flow leads to reduced oxygen and glucose supply and a subsequent switch to the glycolytic pathway, which leads to tissue acidification. Carbonic anhydrase (CA, EC 4.2.1.1) is the enzyme responsible for converting carbon dioxide into a protons and bicarbonate, thus contributing to pH regulation and metabolism, with many CA isoforms present in the brain. Recently, numerous studies have shed light on several classes of carbonic anhydrase inhibitor (CAI) as possible new pharmacological agents for the management of brain ischemia. In the present review we summarized pharmacological, preclinical and clinical findings regarding the role of CAIs in strokes and we discuss their potential protective mechanisms. Full article
(This article belongs to the Special Issue Carbonic Anhydrase and Carbonic Anhydrase Inhibitors)
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