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  1. Fulltext The Role of Extracellular Carbonic Anhydrase in Biogeochemical Cycling: Recent Advances and Climate Change Responses
    Mustaffa NIH, Latif MT, Wurl O
    Int J Mol Sci, 2021 Jul 10;22(14).
    PMID: 34299033 DOI: 10.3390/ijms22147413
    Climate change has been predicted to influence the marine phytoplankton community and its carbon acquisition strategy. Extracellular carbonic anhydrase (eCA) is a zinc metalloenzyme that catalyses the relatively slow interconversion between HCO3- and CO2. Early results indicated that sub-nanomolar levels of eCA at the sea surface were sufficient to enhance the oceanic uptake rate of CO2 on a global scale by 15%, an addition of 0.37 Pg C year-1. Despite its central role in the marine carbon cycle, only in recent years have new analytical techniques allowed the first quantifications of eCA and its activity in the oceans. This opens up new research areas in the field of marine biogeochemistry and climate change. Light and suitable pH conditions, as well as growth stage, are crucial factors in eCA expression. Previous studies showed that phytoplankton eCA activity and concentrations are affected by environmental stressors such as ocean acidification and UV radiation as well as changing light conditions. For this reason, eCA is suggested as a biochemical indicator in biomonitoring programmes and could be used for future response prediction studies in changing oceans. This review aims to identify the current knowledge and gaps where new research efforts should be focused to better determine the potential feedback of phytoplankton via eCA in the marine carbon cycle in changing oceans.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  2. Fulltext Immunocytochemical localization of carbonic anhydrase in the pseudobranch tissue of the rainbow trout Oncorhynchus mykiss
    Rahim SM, Mazlan AG, Simon KD, Delaunoy JP, Laurent P
    J Zhejiang Univ Sci B, 2014 Feb;15(2):194-200.
    PMID: 24510712 DOI: 10.1631/jzus.B1200297
    Pseudobranch function has long interested scientists, but its role has yet to be elucidated. Several studies have suggested that pseudobranchs serve respiratory, osmoregulatory, and sensory functions. This work investigated the immunolocalization of pseudobranch carbonic anhydrase (CA) in the teleost fish species rainbow trout (Oncorhynchus mykiss) to clarify its physiological function. CA was purified from rainbow trout gills O. mykiss and specific antibodies were raised. Immunoblotting between tissue homogenates of pseudobranch and gill CA antibodies showed specific immunostaining with only one band corresponding to CA in the pseudobranch homogenate. Results of immunohistochemical technique revealed that CA was distributed within pseudobranch cells and more precisely in the apical parts (anti-vascular) of cells. The basal (vascular) parts of cells, tubular system, blood capillaries, and pillar cells were not immunostained. Immunocytochemistry confirmed these results and showed that some CA enzyme was cytoplasmic and the remainder was linked to membranous structures. The results also showed that the lacunar tissue layers did not display immunoperoxidase activity. Our results indicated that pseudobranch CA may have a function related to the extracellular medium wherein CA intervenes with the mechanism of stimulation of afferent nerve fibers.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  3. Estrogen and progesterone differentially regulate carbonic anhydrase II, III, IX, XII, and XIII in ovariectomized rat uteri
    Karim K, Giribabu N, Muniandy S, Salleh N
    Syst Biol Reprod Med, 2016;62(1):57-68.
    PMID: 26709452 DOI: 10.3109/19396368.2015.1112699
    Changes in the uterus expression of carbonic anhydrase (CA) II, III, IX, XII, and XIII were investigated under the influence of sex-steroids in order to elucidate mechanisms underlying differential effects of these hormones on uterine pH. Uteri of ovariectomised rats receiving over three days either vehicle, estrogen, or progesterone or three days estrogen followed by three days either vehicle or progesterone were harvested. Messenger RNA (mRNA) and protein levels were quantified by real-time PCR and Western blotting, respectively. The distribution of CA isoenzymes proteins were examined by immunohistochemistry. The levels of CAII, III, XII, and XIII mRNAs and proteins were elevated while levels of CAIX mRNA and protein were reduced following progesterone-only and estrogen plus progesterone treatment, compared to the control and estrogen plus vehicle, respectively. Following estrogen treatment, expression of CAII, IX, XII, and CAXIII mRNAs and proteins were reduced, but remained at a level higher than control, except for CAIX, where its level was higher than the control and following progesterone treatment. Under progesterone-only and estrogen plus progesterone influences, high levels of CAII, III, XII, and XIII were observed in uterine lumenal and glandular epithelia and myometrium. However, a high level of CAIX was observed only under the influence of estrogen at the similar locations. In conclusion, high expression of CAII, III, XII, and XIII under the influence of progesterone and estrogen plus progesterone could result in the reduction of uterine tissue and fluid pH; however, the significance of high levels of CAIX expression under the influence of estrogen remains unclear.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  4. Benzenesulfonamides incorporating bulky aromatic/heterocyclic tails with potent carbonic anhydrase inhibitory activity
    Bozdag M, Alafeefy AM, Vullo D, Carta F, Dedeoglu N, Al-Tamimi AM, et al.
    Bioorg Med Chem, 2015 Dec 15;23(24):7751-64.
    PMID: 26639945 DOI: 10.1016/j.bmc.2015.11.023
    Three series of sulfonamides incorporating long, bulky tails were obtained by applying synthetic strategies in which substituted anthranilic acids, quinazolines and aromatic sulfonamides have been used as starting materials. They incorporate long, bulky diamide-, 4-oxoquinazoline-3-yl- or quinazoline-4-yl moieties in their molecules, and were investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the cytosolic human (h) hCA I and II, as well as the transmembrane hCA IX and XII. Most of the new sulfonamides showed excellent inhibitory effects against the four isoforms, with KIs of 7.6-322nM against hCA I, of 0.06-85.4nM against hCA II; of 6.7-152nM against hCA IX and of 0.49-237nM against hCA XII; respectively. However no relevant isoform-selective behavior has been observed for any of them, although hCA II and XII, isoforms involved in glaucoma-genesis were the most inhibited ones. The structure-activity relationship for inhibiting the four CAs with these derivatives is discussed in detail.
    Matched MeSH terms: Carbonic Anhydrases/metabolism
  5. Synthesis 4-[2-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-ethyl]-benzenesulfonamides with subnanomolar carbonic anhydrase II and XII inhibitory properties
    Bozdag M, Alafeefy AM, Carta F, Ceruso M, Al-Tamimi AS, Al-Kahtani AA, et al.
    Bioorg Med Chem, 2016 09 15;24(18):4100-4107.
    PMID: 27396930 DOI: 10.1016/j.bmc.2016.06.052
    Condensation of substituted anthranilic acids with 4-isothiocyanatoethyl-benzenesulfonamide led to series of heterocyclic benzenesulfonamides incorporating 2-mercapto-quinazolin-4-one tails. These sulfonamides were investigated as inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms hCA I and II (cytosolic isozymes), as well as hCA XII (a transmembrane, tumor-associated enzyme also involved in glaucoma-genesis). The new sulfonamides acted as medium potency inhibitors of hCA I (KIs of 28.5-2954nM), being highly effective as hCA II (KIs in the range of 0.62-12.4nM) and XII (KIs of 0.54-7.11nM) inhibitors. All substitution patterns present in these compounds (e.g., halogens, methyl and methoxy moieties, in positions 6, 7 and/or 8 of the 2-mercapto-quinazolin-4-one ring) led to highly effective hCA II/XII inhibitors. These compounds should thus be of interest as preclinical candidates in pathologies in which the activity of these enzymes should be inhibited, such as glaucoma (CA II and XII as targets) or some tumors in which the activity of isoforms CA II and XII is dysregulated.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  6. Carbohydrazones as new class of carbonic anhydrase inhibitors: Synthesis, kinetics, and ligand docking studies
    Iqbal S, Saleem M, Azim MK, Taha M, Salar U, Khan KM, et al.
    Bioorg Chem, 2017 06;72:89-101.
    PMID: 28390994 DOI: 10.1016/j.bioorg.2017.03.014
    Discovery and development of carbonic anhydrase inhibitors is crucial for their clinical use as antiepileptic, diurectic and antiglaucoma agents. Keeping this in mind, we have synthesized carbohydrazones 1-27 and evaluated them for their in vitro carbonic anhydrase inhibitory potential. Out of twenty-seven compounds, compounds 1 (IC50=1.33±0.01µM), 2 (IC50=1.85±0.24µM), 3 (IC50=1.37±0.06µM), and 9 (IC50=1.46±0.12µM) have showed carbonic anhydrase inhibition better than the standard drug zonisamide (IC50=1.86±0.03µM). Moreover, compounds 4 (IC50=2.32±0.04µM), 5 (IC50=3.96±0.35µM), 7 (IC50=2.33±0.02µM), and 8 (IC50=2.67±0.01µM) showed good inhibitory activity. Cheminformatic analysis has shown that compounds 1 and 2 possess lead-like properties. In addition, kinetic and molecular docking studies were also performed to investigate the binding interaction between carbohydrazones and carbonic anhydrase enzyme. This study has identified a novel and potent class of carbonic anhydrase inhibitors with the potential to be investigated further.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  7. Fulltext Aryl derivatives of 3H-1,2-benzoxathiepine 2,2-dioxide as carbonic anhydrase inhibitors
    Pustenko A, Nocentini A, Balašova A, Alafeefy A, Krasavin M, Žalubovskis R, et al.
    J Enzyme Inhib Med Chem, 2020 Dec;35(1):245-254.
    PMID: 31790605 DOI: 10.1080/14756366.2019.1695795
    A new series of homosulfocoumarins (3H-1,2-benzoxathiepine 2,2-dioxides) possessing various substitution patterns and moieties in the 7, 8 or 9 position of the heterocylic ring were prepared by original procedures and investigated for the inhibition of four physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isoforms, the human (h) hCA I, II, IX and XII. The 8-substituted homosulfocoumarins were the most effective hCA IX/XII inhibitors followed by the 7-substituted derivatives, whereas the substitution pattern in position 9 led to less effective binders for the transmembrane, tumour-associated isoforms IX/XII. The cytosolic isoforms hCA I and II were not inhibited by these compounds, similar to the sulfocoumarins/coumarins investigated earlier. As hCA IX and XII are validated anti-tumour targets, with one sulphonamide (SLC-0111) in Phase Ib/II clinical trials, finding derivatives with better selectivity for inhibiting the tumour-associated isoforms over the cytosolic ones, as the homosulfocoumarins reported here, is of crucial importance.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  8. Fulltext In-vivo functional study on the involvement of CFTR, SLC26A6, NHE-1 and CA isoenzymes II and XII in uterine fluid pH, volume and electrolyte regulation in rats under different sex-steroid influence
    Gholami K, Muniandy S, Salleh N
    Int J Med Sci, 2013;10(9):1121-34.
    PMID: 23869188 DOI: 10.7150/ijms.5918
    Precise control of uterine fluid pH, volume and electrolytes is important for the reproductive processes. In this study, we examined the functional involvement of multiple proteins including Cystic Fibrosis Transmembrane Regulator (CFTR), Cl(-)/HCO3 (-) exchanger (SLC26A6), sodium-hydrogen exchanger-1 (NHE-1) and carbonic anhydrase (CA) in the regulation of these uterine fluid parameters.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  9. Insights on the synthesis of asymmetric curcumin derivatives and their biological activities
    Khor PY, Mohd Aluwi MFF, Rullah K, Lam KW
    Eur J Med Chem, 2019 Dec 01;183:111704.
    PMID: 31557608 DOI: 10.1016/j.ejmech.2019.111704
    Curcumin is a small organic molecule with pleiotropic biological activities. However, its multiple structural-pharmacokinetic challenges prevent its development into a clinical drug. Various structural modifications have been made to improve its drug profile. In this review, we focus on the methods adopted in the synthesis of asymmetric curcumin derivatives and their biological activities and forecast the future of this exciting class of compounds in the field of medicine.
    Matched MeSH terms: Carbonic Anhydrases/metabolism
  10. Probing 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones as multi-target directed ligands against cholinesterases, carbonic anhydrases and α-glycosidase enzymes
    Hashmi S, Khan S, Shafiq Z, Taslimi P, Ishaq M, Sadeghian N, et al.
    Bioorg Chem, 2021 02;107:104554.
    PMID: 33383322 DOI: 10.1016/j.bioorg.2020.104554
    With the fading of 'one drug-one target' approach, Multi-Target-Directed Ligands (MTDL) has become a central idea in modern Medicinal Chemistry. The present study aimed to design, develop and characterize a novel series of 4-(Diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) and evaluates their biological activity against cholinesterase, carbonic anhydrases and α-glycosidase enzymes. The hCA I isoform was inhibited by these novel 4-(diethylamino)-salicylaldehyde-based thiosemicarbazones (3a-p) in low nanomolar levels, the Ki of which differed between 407.73 ± 43.71 and 1104.11 ± 80.66 nM. Against the physiologically dominant isoform hCA II, the novel compounds demonstrated Kis varying from 323.04 ± 56.88 to 991.62 ± 77.26 nM. Also, these novel 4-(diethylamino)-salicylaldehyde based thiosemicarbazones (3a-p) effectively inhibited AChE, with Ki values in the range of 121.74 ± 23.52 to 548.63 ± 73.74 nM. For BChE, Ki values were obtained with in the range of 132.85 ± 12.53 to 618.53 ± 74.23 nM. For α-glycosidase, the most effective Ki values of 3b, 3k, and 3g were with Ki values of 77.85 ± 10.64, 96.15 ± 9.64, and 124.95 ± 11.44 nM, respectively. We have identified inhibition mechanism of 3b, 3g, 3k, and 3n on α-glycosidase AChE, hCA I, hCA II, and BChE enzyme activities. Hydrazine-1-carbothioamide and hydroxybenzylidene moieties of compounds play an important role in the inhibition of AChE, hCA I, and hCA II enzymes. Hydroxybenzylidene moieties are critical for inhibition of both BChE and α-glycosidase enzymes. The findings of in vitro and in silico evaluations indicate 4-(diethylamino)-salicylaldehyde-based thiosemicarbazone scaffold to be a promising hit for drug development for multifactorial diseases like Alzheimer's disease.
    Matched MeSH terms: Carbonic Anhydrases/metabolism
  11. Synthesis of new 3-(2-mercapto-4-oxo-4H-quinazolin-3-yl)-benzenesulfonamides with strong inhibition properties against the tumor associated carbonic anhydrases IX and XII
    Bozdag M, Alafeefy AM, Altamimi AM, Carta F, Supuran CT, Vullo D
    Bioorg Med Chem, 2017 05 15;25(10):2782-2788.
    PMID: 28389112 DOI: 10.1016/j.bmc.2017.03.054
    We report a series of novel metanilamide-based derivatives 3a-q bearing the 2-mercapto-4-oxo-4H-quinazolin-3-yl moiety as tail. All compounds were synthesized by means of straightforward condensation procedures and were investigated in vitro for their inhibition potency against the human (h) carbonic anhydrase (CA; EC 4.2.1.1.1) isoforms I, II, IX and XII. Among all compounds tested the 6-iodo 3g and the 7-fluoro 3i derivatives were the most potent inhibitors against the tumor associated CA IX and XII isoform (KIs 1.5 and 2.7nM respectively for the hCA IX and KIs 0.57 and 1.9nM respectively for the hCA XII). The kinetic data reported here strongly support compounds of this type for their future development as radiotracers in tumor pathologies which are strictly dependent on the enzymatic activity of the hCA IX and XII isoforms.
    Matched MeSH terms: Carbonic Anhydrases/metabolism
  12. Effects of Marantodes pumilum (Kacip Fatimah) on vaginal pH and expression of vacoular ATPase and carbonic anhydrase in the vagina of sex-steroid deficient female rats
    Giribabu N, Karim K, Salleh N
    Phytomedicine, 2018 Oct 01;49:95-105.
    PMID: 30217266 DOI: 10.1016/j.phymed.2018.05.018
    BACKGROUND: In sex-steroid deficiency, increased in the pH of vaginal fluid is due to low estrogen levels.

    HYPOTHESIS: Consumption of Marantodes pumilum leaves helps to ameliorate increased in vaginal fluid pH in sex-steroid deficient condition.

    PURPOSE: To investigate changes in vaginal fluid pH and expression of proteins that participate in pH changes i.e vacoular (V)-ATPases and carbonic anhydrases (CA) in the vagina following M. pumilum leaves consumption.

    METHODS: Ovariectomized adult female rats were treated orally with M. pumilum leaves extract (MPE) at 100, 250 and 500 mg/kg.b.w and estradiol at 0.2 µg/kg/b.w for 28 days. At the end of the treatment, vaginal fluid pH was measured in anesthetised rats by using micropH probe. Following sacrificed, levels of V-ATPase and CA proteins and mRNAs in the vagina were identified by Western blotting and real-time PCR, respectively. Protein distribution was visualized by immunohistochemistry.

    RESULTS: Administration of MPE causes the pH of vaginal fluid to decrease and expression and distribution of vaginal V-ATPase A & B and CA II, III, IX, XII and XIII to increase.

    CONCLUSIONS: The decrease in vaginal fluid pH following MPE treatment suggested that this herb has potential to be used to ameliorate vaginal fluid pH changes in sex-steroid deficient condition.

    Matched MeSH terms: Carbonic Anhydrases/metabolism*
  13. Coumarins and other fused bicyclic heterocycles with selective tumor-associated carbonic anhydrase isoforms inhibitory activity
    Bozdag M, Alafeefy AM, Altamimi AM, Vullo D, Carta F, Supuran CT
    Bioorg Med Chem, 2017 01 15;25(2):677-683.
    PMID: 27939347 DOI: 10.1016/j.bmc.2016.11.039
    Herein we report for the first time a series of 2-benzamido-N-(2-oxo-4-(methyl/trifluoromethyl)-2H-chromen-7-yl) benzamide 3a-f and substituted quinazolin-4(3H)-ones and 2H-benzo[e][1,2,4]thiadiazin-3(4H)-one 1,1-dioxides (5, 6, 8 and 10a-c) as selective inhibitors of the tumor associated hCA IX and XII isoforms. Among the compounds reported the trifluoromethyl derivative 3d resulted the most potent against these CA isoforms with KIs of 10.9 and 6.7nM.
    Matched MeSH terms: Carbonic Anhydrases/metabolism*
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