The effects of some bromophenols on human

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The effects of some bromophenols on human carbonic anhydrase isoenzymes a

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Parham Taslimi , İlhami Gülçin , Necla Öztaşkın , Yasin Çetinkaya , Süleyman Göksu , Saleh b

H. Alwasel & Claudiu T. Supuran

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Department of Chemistry, Faculty of Science, Atatürk University, Erzurum, Turkey,

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Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia,

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Department of Food Technology, Oltu Vocational School, Atatürk University, Oltu, Erzurum, Turkey, d

Dipartimento di Chimica Ugo Schiff, Universita degli Studi di Firenze, Sesto Fiorentino, Firenze, Italy, and e

Section of Pharmaceutical and Nutriceutical Sciences, Neurofarba Department, Universita Degli Studi di Firenze, Sesto Fiorentino, Florence, Italy Published online: 03 Jul 2015. To cite this article: Parham Taslimi, İlhami Gülçin, Necla Öztaşkın, Yasin Çetinkaya, Süleyman Göksu, Saleh H. Alwasel & Claudiu T. Supuran (2015): The effects of some bromophenols on human carbonic anhydrase isoenzymes, Journal of Enzyme Inhibition and Medicinal Chemistry To link to this article: http://dx.doi.org/10.3109/14756366.2015.1054820

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http://informahealthcare.com/enz ISSN: 1475-6366 (print), 1475-6374 (electronic) J Enzyme Inhib Med Chem, Early Online: 1–5 ! 2015 Informa UK Ltd. DOI: 10.3109/14756366.2015.1054820

RESEARCH ARTICLE

The effects of some bromophenols on human carbonic anhydrase isoenzymes Parham Taslimi1, _Ilhami Gu¨lçin1,2, Necla O¨zta¸skın1, Yasin Çetinkaya3, Su¨leyman Go¨ksu1, Saleh H. Alwasel2, and Claudiu T. Supuran4,5

Downloaded by [Ataturk University] at 08:06 05 August 2015

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Department of Chemistry, Faculty of Science, Atatu¨rk University, Erzurum, Turkey, 2Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia, 3Department of Food Technology, Oltu Vocational School, Atatu¨rk University, Oltu, Erzurum, Turkey, 4 Dipartimento di Chimica Ugo Schiff, Universita degli Studi di Firenze, Sesto Fiorentino, Firenze, Italy, and 5Section of Pharmaceutical and Nutriceutical Sciences, Neurofarba Department, Universita Degli Studi di Firenze, Sesto Fiorentino, Florence, Italy Abstract

Keywords

Carbonic anhydrases (CAs, EC 4.2.1.1), which are involved in a variety of physiological and pathological processes, are ubiquitous metalloenzymes mainly catalyzing the reversible + hydration of carbon dioxide (CO2) to bicarbonate (HCO 3 ) and proton (H ). In this study, a dozen of bromophenol derivatives (1–12) were evaluated as metalloenzyme CA (EC 4.2.1.1) inhibitors against the human carbonic anhydrase isoenzymes I and II (hCA I and II). Cytosolic hCA I and II isoenzymes were effectively inhibited by bromophenol derivatives (1–12) with Kis in the low nanomolar range of 1.85 ± 0.58 to 5.04 ± 1.46 nM against hCA I and in the range of 2.01 ± 0.52 to 2.94 ± 1.31 nM against hCA II, respectively.

Bromophenols, carbonic anhydrase, enzyme inhibition, enzyme purification, isoenzymes

Introduction Carbonic anhydrases (CAs, EC 4.2.1.1) are biological catalysts for the interconversion of carbon dioxide (CO2) and water to + 1–3 : bicarbonate (HCO 3 ) and a proton (H ) þ CO2 þ H2 O , HCO 3 þ H

CAs are polifunctional enzymes which play a crucial role in different physiological and biochemical processes such as acid– base homeostasis, respiratory gas exchange, ionic transport, electrolytes secretion, muscular contraction in vertebrates, photosynthesis in cyanobacteria, plants and algae, synthesis of fatty acids, biosynthetic reactions including ureagenesis and gluconeogenesis4–7. Recently, many studies revealed that CAs are also widely distributed in prokaryotes8. Indeed, six distinct CA classes are known to date: a-, b-, g-, d-, z- and Z-CAs9–11. a-CAs have normally monomer structures and rarely dimer form. b-CAs are dimers, tetramers or octamers, g-CAs are trimers, whereas the dand z-CAs are less well understood up to now8. In humans, 15 different a-CA isoforms were described so far, which differ by molecular features, oligomeric arrangement, cellular localization, distribution in organs and tissues, expression levels and kinetic properties12–14. These CAs comprise CA I, II, III, IV, VA, VB, VI, VII, IX, XII, XIII and XIV, all of which contain a zinc ion (Zn2+)

_ Address for correspondence: Prof. Dr. Ilhami Gu¨lçin, Department of Chemistry, Faculty of Science, Atatu¨rk University, 25240 Erzurum, Turkey. Tel: +90 4422314375. Fax: +90 4422314109. E-mail: [email protected]

History Received 10 May 2015 Revised 15 May 2015 Accepted 19 May 2015 Published online 2 July 2015

in their active site, coordinated to the imidazole groups of three histidine residues and to a water molecule (H2O)/hydroxide ion (–OH) the substrate that reacts with CO215–18. There are five cytosolic forms (CA I, II, III, VII and XIII), five membrane associated isozymes (CA IV, IX, XII, XIV and XV), two mitochondrial forms (CA VA and VB) and a secreted CA isoenzyme (CA VI). There are three additional non-catalytic CA isoforms (CA VIII, X and XI) whose functions remain unclear19–21. CA inhibitors (CAIs) are clinically used as diuretics and antiglaucoma drugs. In addition, CAIs could have potential as antiobesity, anti-cancer and anti-infective drugs22–25. Naturally occurring bromophenols are important in synthetic organic chemistry and medicinal chemistry. These compounds are mostly isolated in marine life, especially from marine algae26–28. As it can be seen from the brief description given above, bromophenols show useful biological activities. In our previous studies, we synthesized bromophenols containing polybromides in their structures. In this study, we determined the effects of a dozen of bromophenol derivatives (1–12) on cytosolic hCA I, and II isoenzymes.

Experimental Affinity chromatography is a purification method of separating biochemical mixtures based on a highly specific interaction such as that between enzyme and substrate29. In this study, both CA isoenzymes were purified by Sepharose-4B-L-tyrosine-sulfanilamide affinity chromatography in a single step30–32. The column material including Sepharose-4B-L-tyrosine-sulfanilamide was prepared according to a previous method33–35. Thus, homogenate

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Figure 1. The chemical structure of bromophenol derivatives (1–12).

solution acidity was adjusted and supernatant was transferred to the previously prepared Sepharose-4B-L-tyrosine-sulphanilamide affinity column36–38. The proteins flow in the column eluates was spectrophotometrically determined at 280 nm. For determination of both isoenzymes purity, sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE) for both isoenzymes was performed after purification step. This technique widely used in biochemistry, forensics, genetics, molecular biology and biotechnology for the separation of biological macromolecules including proteins according to their electrophoretic mobility. The presence and purity of both isoenzymes were visualized by SDS–PAGE. After this process, a single band was observed for each isoenzyme39. This protein imaging method was previously described40–42. In this application, the imaging method was performed out in 10% and 3% acrylamide for the running and the stacking gel, respectively, with 0.1% SDS43,44. Both CA isoenzymes activities were determined according to the method of Verpoorte et al.45 and described previously46,47. The protein quantity was spectrophotometrically measured at 595 nm during the purification steps according to the Bradford method48. Bovine serum albumin was used as the standard protein49. For determining the inhibition effect of each bromophenol derivative, an activity (%)–[Bromophenols] graph was drawn. To determine Ki values, three different bromophenols concentrations were tested. In these experiments, different substrate concentration was used and Lineweaver–Burk curves were drawn50,51 as previously described52.

Results and discussion Naturally occurring bromophenols compounds are abundantly found in marine life. They were frequently isolated from red algae of the family Rhodomelaceae and had some important biological activities53–55. It was reported that the bromophenol derivatives coordinate to the active site Zn2+ and to block the reaction catalysis. For example, (4,5-dihydroxy-2-methylphenyl)(3,4-dihydroxyphenyl)methanone was found much more effective inhibitors against hCA I and II38. In another study, it was found that hCA I, II and VI were inhibited by a series of bisphenol and bromophenol derivatives27. Recently, Balaydın et al. determined CA I, II, IV and VI inhibition effects of novel cyclohexanonyl bromophenol derivatives including naturally occurring novel cyclohexanonyl bromophenol 2(R)-2-(2,3,6-tribromo-4,5-dihydroxybenzyl)cyclohexanone and some of them showed interesting inhibitory profile28. In a recent study, it was demonstrated that dimethoxy-bromophenol derivatives incorporating cyclopropane moieties have shown picomolar inhibition against cytosolic CA I, II and tumor-associated CA IX, and XII9. The relationship between anti-oxidant molecules and CA isoenzyme inhibition is well established56–58. It is well known that bromophenol derivatives had some biological activities including anti-oxidant and radical scavenging55, acetylcholine esterase inhibition properties55,59. The clinical usage of CAIs has been established as antiglaucoma agents, diuretics and anti-epileptic. CAIs were also used in the treatment of mountain sickness, osteoporosis, gastric and duodenal ulcers and neurological disorders60–62.

CA inhibition of novel bromophenol derivatives

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Table 1. Human carbonic anhydrase isoenzymes I and II inhibition profile of bromophenol derivatives (1–12). IC50 (nM) Bromophenols 1 2 3 4 5 6 7 8 9 10 11 12 AZAa

hCA I

2

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2.63 3.16 2.63 2.93 3.62 2.77 2.93 2.56 2.73 3.01 3.05 4.17 6.07

0.9795 0.9811 0.9721 0.9813 0.9810 0.9744 0.9859 0.9660 0.9843 0.9570 0.9658 0.9866 0.9154

KI (nM)

hCA II

r

2

hCA I

hCA II

2.23 2.46 2.22 2.38 3.02 2.30 2.53 2.22 2.63 2.45 2.17 2.66 5.50

0.9833 0.9705 0.991 0.9606 0.9919 0.9874 0.9918 0.979 0.9943 0.9897 0.9923 0.9934 0.9636

2.28 ± 0.82 3.12 ± 1.19 1.85 ± 0.58 2.26 ± 0.39 3.38 ± 1.04 2.46 ± 0.47 3.14 ± 1.32 2.04 ± 0.47 3.04 ± 1.50 3.02 ± 1.25 2.80 ± 0.93 5.04 ± 1.46 6.76 ± 2.55

2.32 ± 0.41 2.58 ± 0.38 2.78 ± 1.03 2.06 ± 0.80 2.75 ± 0.67 2.29 ± 0.96 2.53 ± 0.86 2.12 ± 0.90 2.29 ± 1.01 2.91 ± 1.21 2.01 ± 0.52 2.94 ± 1.31 5.85 ± 2.56

a


Acetazolamide (AZA) was used as a standard inhibitor for both hCA enzymes.

Both physiologically relevant hCA I, and II isoforms were included in our study. A dozen of bromophenol derivatives (1–12) were evaluated for their inhibition properties against hCA I and II isoenzymes, showing generally an efficient inhibition. The chemical structures of bromophenol derivatives (1–12) are given in Figure 1. Also, CA I and II inhibiting effects of a dozen of bromophenol derivatives (1–12) are shown in Table 1. It was well known that developing isoenzyme-specific CAIs should be highly beneficial in obtaining novel classes of drugs devoid of various undesired side-effects25. We declare here the first study on the inhibitory effects of a dozen of bromophenol derivatives (1–12) against hCA I and II using esterase activity. Low cytosolic isoenzyme hCA I is found in many tissues, however, it was demonstrated that this isoenzyme is involved in retinal and cerebral edema, and its inhibition may be a valuable tool for fighting these conditions. Also, it was reported that if Ki value of a dozen of bromophenol derivatives (1–12) was less than 10 nM (Kis510 nM). The results obtained from this study clearly indicate that a dozen of bromophenol derivatives (1–12) had effective inhibition profile against slow cytosolic isoform hCA I, and cytosolic dominant rapid isozymes hCA II with low nanomolar range (Kis510 nM). These compounds bind to hCA I in the nanomolar range. Ki values are ranging in 1.85 ± 0.58 to 5.04 ± 1.46 nM for hCA I isoenzyme. However, acetazolamide (AZA) considered being a broad-specificity CAI owing to its widespread inhibition of CAs, demonstrated showed Ki value of 6.76 ± 2.55 nM against hCA I. Bromophenol (3), possessing three methoxy (–OCH3) and a bromine (–Br) group, was the best hCA II inhibitor (Ki: 1.79 ± 0.22 nM). It is well known that the molecules, which had three –OCH3 and a –Br group, demonstrated effective CA isoenzyme inhibition properties9,10. The inhibition effects of all bromophenol derivatives (1–12) are higher than that of acetazolamide (AZA; Ki: 6.76 ± 2.55 nM). AZA, 5-acetamido-1,3,4-thiadiazole-2-sulfonamide, is considered the good CAI and is approved for the treatment of a range of conditions including glaucoma, epilepsy and altitude sickness5. CA II is involved in several diseases including epilepsy, edema, altitude sickness and glaucoma. Against the physiologically dominant isoform hCA II, all bromophenol derivatives (1–12) demonstrated Kis of 2.01 ± 0.52 to 2.94 ± 1.31 nM (Table 1). The bromophenol 11, which had two methoxy (–OH) and a bromine (–Br) groups, was the best hCA II inhibitor (Ki: 2.01 ± 0.52 nM). Phenolic compounds have a lot of nutritional and pharmacological properties including anti-oxidant properties62–81 and enzymes inhibition82–86. However, all bromophenol derivatives (1–12) have shown similar hCA II inhibition properties. These results showed that all bromophenol derivatives (1–12)

had higher affinity toward hCA II than that of hCA I isoform. Also, AZA, which may interact with the distinct hydrophobic and hydrophilic halves of the CA II active site, showed Ki value of 5.85 ± 2.56 nM. This standard demonstrated less inhibition activity than that of all bromophenol derivatives (1–12).

Conclusion In conclusion, a dozen of bromophenol derivatives (1–12) were evaluated against cytosolic hCA I and II. These bromophenols have shown nanomolar inhibition against cytosolic CA I and II. Novel bromophenols were found to be effective hCA I and II inhibitors. Both isoenzymes were potently inhibited by bromophenol derivatives (1–12) with Kis in the range of 1.85 ± 0.58 to 5.04 ± 1.46 nM against hCA I and in the range of 2.01 ± 0.52 to 2.94 ± 1.31 nM against hCA II, respectively.

Acknowledgement I.G. and S.H.A. would like to extend their sincere appreciation to the Research Chairs Program at King Saud University for funding this research.

Declaration of interest The authors report there is no conflict of interests.

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