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Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds
Arabian Journal of Chemistry (2014) xxx, xxx–xxx
King Saud University
Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com
ORIGINAL ARTICLE
Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds Hulya Go¨cer a b c
a,b
, Akın Akıncıog˘lu
_ Gu¨lc¸in , Su¨leyman Go¨ksu a, Ilhami
a,b
a,c,*
Department of Chemistry, Faculty of Science, Atatu¨rk University, 25240-Erzurum, Turkey Agri Ibrahim Cecen University, Central Researching Laboratory, 04100-Agri, Turkey Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
Received 27 November 2013; accepted 20 August 2014
KEYWORDS Phenolic sulfonamides; Carbonic anhydrase; Enzyme inhibition; Carbonic anhydrase
Abstract The effects of some phenolic sulfonamides were determined on the cytosolic carbonic anhydrase isoenzyme I and II (hCA I and II). Both isoenzymes were purified separately from human erythrocytes, using the Sepharose-4B-L-tyrosine-sulfanilamide affinity column chromatography method. In continuation of the study, we identified the inhibitory effects of phenolic sulfonamides 1–4 on the esterase activity of hCA I, and II. The inhibitory effects of phenolic sulfonamides 1–4 were tested on human carbonic anhydrase isoenzymes hCA I, and II. Among the compounds 1– 4, compound 1 was concluded to show the best inhibitory effects. According to our data, IC50 values of compound 1 were found as 3.55 and 2.94 lM for hCA I, and hCA II, respectively. On the other hand, Ki values of this compound were found as 0.827 and 0.745 lM for both isoenzymes, respectively. ª 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction * Corresponding author. Address: Atatu¨rk University, Faculty of Sciences, Department of Chemistry, TR-25240-Erzurum, Turkey. Tel.: +90 442 2314375; fax: +90 442 2360948. E-mail addresses: [email protected], [email protected] _ Gu¨lc¸in). (I. Peer review under responsibility of King Saud University.
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Carbonic anhydrase (CA: EC 4.2.1.1.) is a metalloenzyme containing a Zn2+ ion. CA is a very important enzyme, which regulates CO2 levels in living organisms. CA was first isolated from mammalian erythrocyte (Gu¨lc¸in et al., 2004; Gu¨ney et al., 2014). It was reported that CA was isolated, purified and characterized from many different plant and animal tissues (Gu¨lc¸in et al., 2004; Topal and Gu¨lc¸in, 2014). All these enzymes catalyze the reactions as shown below: þ CO2 þ H2 O H2 CO3 HCO 3 þH
http://dx.doi.org/10.1016/j.arabjc.2014.08.005 1878-5352 ª 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
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H. Go¨cer et al.
CA has active properties in the kidney, gastric mucosa, eye lens, salivary glands, brain, nerve myelin sheath, pancreas, prostate and uterus (Gu¨lc¸in and Beydemir, 2013; Arabaci et al., 2014). CA isoforms participate in several important biological processes and they are found in a variety of tissues. Studies demonstrated important roles of CAs in a variety of physiological procedures, and showed that extraordinary levels or activities of these enzymes have been often related with different human diseases (Innocenti et al., 2010a; Go¨c¸er et al, 2014). CA inhibitors (CAIs) are classified into two main groups, the metal complexing anions and the unsubstituted sulfonamides. Sulfonamides are very important CAIs. Anions may bind either in a tetrahedral geometry with the metal ions or as a trigonal-bipyramidal adduct. Sulfonamides bind in a tetrahedral geometry with the Zn2+ ions (Bertini et al., 1982; Lindahl et al., 1990; Briganti et al., 1996; Supuran and Scozzafava, 2000; Kim et al., 2000). E Zn2þ OH2 þ I $ E Zn2þ I þ H2 O E Zn2þ OH2 þ I $ E Zn2þ H2 OðIÞ The discovery of CA inhibition with sulfanilamide by Mann and Keilin (1940) was the beginning of many scientific discoveries and applications. Important drugs, such as antihypertensives of benzothiadiazine and high-ceiling diuretics were prepared following the discovery (Maren, 1967). More than 100 sulfonamides were investigated by means of kinetic, physiological and pharmacological studies. Following these, many studies were performed for preparing aromatic sulfonamides, which were investigated for their CA inhibitory action. Among the aromatic sulfonamides, benzene sulfonamides have shown the best CA inhibitory action (Supuran et al., 2004). Over the years many different sulfonamides have been reported to act as CAIs. One of the most investigated compounds is phenol (Go¨ksu et al., 2014). After many studies, excellent results have been achieved, especially associated with sulfonamides and their derivatives. In 1982 Lindskog’s group reported that phenols act as competitive inhibitors against human cytosolic CA II (Tibell et al., 1985; Simonsson et al., 1982). Also, extra structural description on the binding mode of phenolic compounds or derivatives to the CA active site has been clarified (Supuran and Scozzafava 2002). In this context, we aimed to extend our study on the CA inhibitory properties of some phenolic sulfonamides. Table 1
2. Result and discussion 2.1. CA purification and activity assay In this study, hCA I, and II isoenzymes were purified separately from human fresh erythrocytes, using a simple one-step chromatographic method using Sepharose-4B-L-tyrosine-sulfanilamide column material. In the first part of our study, we have identified the inhibitory effects of phenolic sulfonamides 1–4 on the esterase activity of both isoenzymes (Table 1). In one of our early studies we have reported the synthesis, acetylcholinesterase inhibitory and antioxidant activity of compounds 1–4 (Go¨c¸er et al., 2013). The inhibition measurements were performed with esterase activity methods described by Akincioglu et al. (2013a,b). The base of this method is based on the destruction of CA ester bonds. In this process, the CA enzyme hydrolyzes the phenyl acetate and the resulting product showed absorption at 348 nm. In our study, this method was preferred due to its high sensitivity compared to methods of Wilbur and Anderson (1948). 2.2. CA isoenzymes inhibitory effects CAIs have been essentially used as diuretics and antiglaucoma agents (Winum et al., 2006; Supuran 2007, 2008; De Simone et al, 2008; Hen et al., 2011). In recent studies for the synthesis of CAIs, the sulfonamide compounds (R-SO2NH2) are very important and widely used in zinc binding functions (Akıncıog˘lu et al., 2013a; Akbaba et al., 2013a; C¸etinkaya et al., 2013; Aksu et al., 2013). They are designed and synthesized according to these characteristics. We firstly reported the study on the inhibitory effects of synthesized novel sulfonamides 1–4 and on the esterase activity of hCA I, and II. In this study inhibitory effects of compounds on the CA isoenzymes were investigated. Results were determined for hCA I, and II by drawing Lineweaver-Burk graphs (1934). After hCA I, and II inhibitory effects of the novel phenolic sulfonamides 1–4 the IC50 and average Ki values were calculated. The results given in Table 2 show the following regarding the inhibitory effects of hCA I, and II by novel phenolic sulfonamides 1–4. CA isoenzyme inhibitors block the active site of CA isoenzymes and in this way the actual metabolism of the substrate is inhibited and the body functions remain normal (Shahwar et al., 2012). In the current study, we demonstrated strong
The chemical structure of phenolic sulfonamides 1–4. Compounds
R1
R2
R3
R4
R5
1
OH
H
H
H
H
2 3 4
H H OH
OH OH OH
OH H H
H OH H
H H H
O
R1 H N
R2
S
CH3
O R3
R5 R4
Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
Sulfonamides inhibit carbonic anhydrase
3
Table 2 Human carbonic anhydrase isoenzyme (hCA I and hCA II) inhibition value with some phenolic sulfonamide derivatives (1–4) by an esterase assay with 4-nitrophenylacetate as substrate. Compounds
1 2 3 4
IC50 (lM)
KI (lM)
hCA I
R2
hCA II
R2
hCA I
hCA II
3.55 3.60 3.43 5.41
0.997 0.995 0.961 0.985
2.94 2.42 3.43 4.07
0.985 0.989 0.9632 0.994
0.827 ± 0.096 2.508 ± 0.099 1.884 ± 0.098 1.592 ± 0.033
0.745 ± 0.173 0.919 ± 0.019 0.867 ± 0.034 1.046 ± 0.008
inhibitory effects of newly synthesized phenolic sulfonamide compounds (1–4) on both cytosolic isoenzymes. The arithmetic average Ki values of sulfonamides compounds (14) are in the range of 0.827–2.508 lM for hCA I, and 0.745–1.046 lM for hCA II (Table 2). Half-maximum inhibitory concentration (IC50) measures the effectiveness of novel phenolic sulfonamides 1–4 in inhibiting CA isoenzyme function. Lower IC50 and Ki values show strong CA isoenzyme inhibitory effects of sulfonamides. These data are very important for biologically active compounds. In the last years, a lot of sulfonamide drug groups have been developed in the drug markets (Supuran and Scozzafava 2000). At first, Lindskog’s group (Simonsson et al., 1982) reported phenols as inhibitors against human CA II and extra structural definition on the binding mode of phenolic derivatives to the CA active site was obtained (Supuran and Scozzafava 2002). CA inhibitory effects of a large spectrum of phenolic compounds including melatonin (Beydemir and Gu¨lc¸in, 2004), morphine (C¸oban et al., 2007), vitamin E (ArasHisar et al., 2004), caffeic acid phenethyl ester (Go¨c¸er and Gu¨lc¸in, 2013), a series of antioxidant phenols (Sentu¨rk et al., 2009), a series of phenolic acids (Ozturk Sarikaya et al., 2010), a series of natural product polyphenols and phenolic acids (Innocenti et al., 2010a,b), two different series of natural phenolic compounds (Sentu¨rk et al., 2011; Ozturk Sarikaya et al., 2011; Gu¨lc¸in and Beydemir, 2013), antioxidant polyphenol natural products (Innocenti et al., 2010b), (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives (Nar et al., 2013), natural and synthetic bromophenols (Akbaba et al. 2013b; Balaydın et al. 2012a,b), novel phenolic sulfonamides (Akıncıog˘lu et al., 2013b), novel sulfonamide derivatives of aminoindanes and aminotetralins (Akbaba et al., 2013b), novel phenolic benzylamine derivatives (C¸etinkaya et al., 2013), sulfonamide analogs of dopamine related compounds (Aksu et al., 2013), new benzotropons (Gu¨ney et al., 2014) and novel sulfonamides incorporating tetralin scaffold (Akıncıog˘lu et al., 2013b) have been reported. These extensive studies indicate the importance of CA enzyme inhibitors. The results obtained from Table 2 clearly show that the physiologically dominant cytosolic isozymes hCA I, and II were effectively inhibited by sulfonamide compounds 1–4. The reason for this is that both cytosolic isoenzymes have a high sequence of amino acid homology within their active sites (Xue et al., 1993; Brzozowski et al., 2012). Sulfonamides 1–4 have one aromatic ring and –OH groups. Here, compounds 1–4 have been studied as hCA isoenzymes inhibitors. The logic of working these sulfonamides as potent CA inhibitors exists in the fact that the compounds with aromatic rings have been identified to be the inhibitor with CO2 as the substrate for the main isoform of CA.
3. Conclusion In conclusion, acetylcholine esterase inhibitors and antioxidant sulfonamides 1–4 were evaluated for CA inhibitory properties. In this study, micromolar levels of Ki and IC50 values were observed. We show by this study that compounds 1–4 are both selective cytosolic CA isoenzyme inhibitors with selectivity ratios in the range of 0.745–2.508 lM. These results clearly indicate that phenolic sulfonamides 1–4 may be used as leads for generating both powerful cytosolic CA inhibitors eventually targeting other isoforms. 4. Experimental 4.1. General information The chemicals and solvents used in this study are commercially available. All solvents were purified according to standard procedures. CA inhibitory properties of samples were determined using a spectrophotometer (UV-1208, Shimadzu, Japan). Compounds 1–4 were synthesized according to our previous procedure (Go¨c¸er et al., 2013). 4.2. Purification of CA isoenzymes CA isoenzymes were purified via a simple single-step method Sepharose-4B-L-tyrosine-sulfanilamide affinity gel chromatography (Atasaver et al., 2013), as defined previously (Ozturk Sarikaya et al., 2010; Sentu¨rk et al., 2011). Fresh human erythrocyte samples were centrifuged at 10,000g for 30 min and then removed and the serum isolated. The pH was adjusted to 8.7 with solid Tris. Sepharose-4B-L-tyrosine-sulfanilamide affinity column equilibrated with Tris–HCl (25 mM)/Na2SO4 (0.1 M; pH 8.7). The Sepharose-4B-L-tyrosine-sulfanilamide affinity gel was washed with Tris–HCl (25 mM)/Na2SO4 (22 mM) at pH 8.7. Both CA isozymes were eluted with NaCl (1.0 M)/Na2 HPO4 (25 m) at pH 6.3 and NaCH3COO (0.1 M)/NaClO4 (0.5 M) at pH 5.6, respectively. During both isozymes purification procedures, proteins stream was monitored at 280 nm (Beydemir and Gu¨lc¸in 2004; Go¨c¸er and Gu¨lc¸in, 2013). 4.3. Esterase activity assay and protein determination A spectrophotometric method (SHIMADZU, UVmini-1240 UV–VIS Spectrophotometer) was used for the determination of carbonic anhydrase activities (Verpoorte et al. 1967). This method was previously described (Hisar et al., 2005a; Gu¨lc¸in and Beydemir, 2013). The change in absorbance at 348 nm of 4-nitrophenylacetate (NPA) to 4-nitrophenylate was recorded
Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
4 for 3 min at 25 C. The control medium contained 1.4 mL TrisSO4 buffer (0.05 M, pH 7.4), 4-nitrophenylacetate (1 mL, 3 mM), H2O (0.5 mL) and enzyme solution (0.1 mL). Final volume reached 3.0 mL. The control was obtained by preparing the mixture without the enzyme solution. All measurements were recorded as triplicate. The Ki values were determined from a series of experiments using three different phenolic sulfonamide compound (1–4) concentrations and NPA as the substrate at five different concentrations for the construction of Lineweaver-Burk curves (1934) described previously (Hisar et al., 2005b; Sentu¨rk et al., 2008). Furthermore the quantity of protein during every purification step was determined spectrophotometrically at 595 nm according to the Bradford method (1976). As in other studies, bovine serum albumin was used as standard protein in this study (Gu¨lc¸in et al., 2005). 4.4. SDS–polyacrylamide gel electrophoresis The purity of the enzymes was confirmed using SDS–polyacrylamide gel electrophoresis (SDS–PAGE). The running and stacking gels contained 10% and 3% acrylamide, respectively, and 0.1% SDS, according to the Laemmli procedure (1970) described previously (Sisßeciog˘lu et al., 2009, 2010). To each electrophoresis medium a 20 mg sample aliquot was applied. SDS–polyacrylamide gel was painted with Coomassie brilliant blue R-250 reagent over night. Then, the electrophoretic zymogram was photographed (Ko¨ksal et al., 2012). Acknowledgments The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at the King Saud University for funding this research through the Research Group Project no. RGP-VPP-254. References _ Akbaba, Y., Akıncıog˘lu, A., Go¨c¸er, H., Go¨ksu, S., Gu¨lc¸in, I., Supuran, C.T., 2013a. Carbonic anhydrase inhibitory properties of novel sulfonamide derivatives of aminoindanes and aminotetralins. J. Enzyme Inhib. Med. Chem. 29, 35–42. Akbaba, Y., Balaydın, H.T., Menzek, A., Go¨ksu, S., S ß ahin, E., Ekinci, D., 2013b. Synthesis and biological evaluation of novel bromophenol derivatives as carbonic anhydrase inhibitors. Arch. Pharm. 346, 447–454. _ Akıncıog˘lu, A., Akbaba, Y., Go¨c¸er, H., Go¨ksu, S., Gu¨lc¸in, I., Supuran, C.T., 2013a. Novel sulfamides as potential carbonic anhydrase isoenzymes inhibitors. Bioorg. Med. Chem. 21, 379– 1385. _ Go¨ksu, S., 2013b. Novel Akıncıog˘lu, A., Topal, M., Gu¨lc¸in, I., sulfamides and sulfonamides incorporating tetralin scaffold as carbonic anhydrase and acetylcholine esterase inhibitors. Arch. Pharm. 347, 68–76. _ Go¨ksu, S., Tu¨mer, Aksu, K., Nar, M., Tanc¸, M., Vullo, D., Gu¨lc¸in, I., F., Supuran, C.T., 2013. The synthesis of sulfamide analogues of dopamine related compounds and their carbonic anhydrase inhibitory properties. Bioorg. Med. Chem. 21, 2925–2931. _ Alwasel, S., 2014. Capsaicin: a potent inhibitor Arabaci, B., Gu¨lc¸in, I., of carbonic anhydrase isoenzymes Molecules 19, 10103–10114. _ Yanık, T., 2004. ArasHisar, S ß ., Hisar, O., Beydemir, S ß ., Gu¨lc¸in, I., Effect of vitamin E on carbonic anhydrase enzyme activity in rainbow trout (Oncorhynchus mykiss) erythrocytes in vitro and in vivo. Acta Vet. Hung. 52, 413–422.
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Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
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5 some phenolic compounds. Bioorg. Med. Chem. Lett. 21, 4259– 4262. _ C¸iftci, M., Ku¨freviog˘lu, O¨.I., _ 2008. Dantrolene S ß entu¨rk, M., Gu¨lc¸in, I., inhibits human erythrocyte glutathione reductase. Biol. Pharm. Bull. 31, 2036–2039. _ Dasßtan, A., Ku¨freviog˘lu, O¨.I., _ Supuran, C.T., Sentu¨rk, M., Gu¨lc¸in, I., 2009. Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols. Bioorg. Med. Chem. 17, 3207–3211. _ Beydemir, S _ Supuran, Sentu¨rk, M., Gu¨lc¸in, I., ß ., Ku¨freviog˘lu, O¨.I., C.T., 2011. In vitro inhibition of human carbonic anhydrase I and II isozymes with natural phenolic compounds. Chem. Biol. Drug Des. 7 (7), 494–499. Shahwar, D., Raza, M.A., Khan, T., 2012. Synthesis and evaluation of enzyme inhibitory potential of some derivatives of scopolamine. Turk. J. Chem. 36, 257–266. Simonsson, I., Jonsson, B.H., Lindskog, S., 1982. Phenol, a competitive inhibitor of CO2 hydration catalyzed by carbonic anhydrase. Biochem. Biophys. Res. Commun. 108, 1406–1412. _ O¨zdemir, M., 2009. The Sisßeciog˘lu, M., C¸ankaya, M., Gu¨lc¸in, I., inhibitory effect of propofol on lactoperoxidase. Protein Pept. Lett. 16, 46–49. _ O¨zdemir, M., 2010. InteracSisßeciog˘lu, M., C¸ankaya, M., Gu¨lc¸in, I., tions of melatonin and serotonin to lactoperoxidase enzyme. J. Enzyme Inhib. Med. Chem. 25, 779–783. Supuran, C.T., 2007. Carbonic anhydrases as drug targets-an overview. Curr. Top. Med. Chem. 7, 825–833. Supuran, C.T., 2008. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat. Rev. Drug Discov. 7, 168– 181. Supuran, C.T., Scozzafava, A., 2000. Carbonic anhydrase inhibitors and their therapeutic potential. Exp. Opin. Ther. Patents 10, 575– 600. Supuran, C.T., Scozzafava, A., 2002. Applications of carbonic anhydrase inhibitors and activators in therapy. Exp. Opin. Ther. Patents 12, 217–242. Supuran, C.T., Casini, A., Scozzafava, A., 2004. In: Supuran, C.T., Scozzafava, A., Conway, J. (Eds.), Carbonic Anhydrase: Its inhibitors and Activators. CRC Press, Boca Raton, FL, p. 67. Tibell, L., Forsman, C., Simonsson, I., Lindskog, S., 1985. Anion inhibition of CO2 hydration catalyzed by human carbonic anhydrase II. Mechanistic implications. Biochim. Biophys. Acta 829, 302–310. _ 2014. Rosmarinic acid: a potent carbonic Topal, M., Gu¨lc¸in, I., anhydrase isoenzymes inhibitor. Turk. J. Chem. 38, 894–902. Verpoorte, J.A., Mehta, S., Edsall, J.T., 1967. Esterase activities of human carbonic anhydrases B and C. J. Biol. Chem. 242, 4221– 4229. Wilbur, K.M., Anderson, N.G., 1948. Electrometric and colorimetric determination of carbonic anhydrase. J. Biol. Chem. 176, 147–154. Winum, J.Y., Scozzafava, A., Montero, J.L., Supuran, C.T., 2006. New zinc binding motifs in the design of selective carbonic anhydrase inhibitors. Mini Rev. Med. Chem. 6, 921–936. Xue, Y., Liljas, A., Jonsson, B.H., Lindskog, S., 1993. Crystallographic analysis of Thr-200 fi His human carbonic anhydrase II and its complex with the substrate, HCO 3 . Proteins 15, 80–87.
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ORIGINAL ARTICLE
Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds Hulya Go¨cer a b c
a,b
, Akın Akıncıog˘lu
_ Gu¨lc¸in , Su¨leyman Go¨ksu a, Ilhami
a,b
a,c,*
Department of Chemistry, Faculty of Science, Atatu¨rk University, 25240-Erzurum, Turkey Agri Ibrahim Cecen University, Central Researching Laboratory, 04100-Agri, Turkey Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
Received 27 November 2013; accepted 20 August 2014
KEYWORDS Phenolic sulfonamides; Carbonic anhydrase; Enzyme inhibition; Carbonic anhydrase
Abstract The effects of some phenolic sulfonamides were determined on the cytosolic carbonic anhydrase isoenzyme I and II (hCA I and II). Both isoenzymes were purified separately from human erythrocytes, using the Sepharose-4B-L-tyrosine-sulfanilamide affinity column chromatography method. In continuation of the study, we identified the inhibitory effects of phenolic sulfonamides 1–4 on the esterase activity of hCA I, and II. The inhibitory effects of phenolic sulfonamides 1–4 were tested on human carbonic anhydrase isoenzymes hCA I, and II. Among the compounds 1– 4, compound 1 was concluded to show the best inhibitory effects. According to our data, IC50 values of compound 1 were found as 3.55 and 2.94 lM for hCA I, and hCA II, respectively. On the other hand, Ki values of this compound were found as 0.827 and 0.745 lM for both isoenzymes, respectively. ª 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
1. Introduction * Corresponding author. Address: Atatu¨rk University, Faculty of Sciences, Department of Chemistry, TR-25240-Erzurum, Turkey. Tel.: +90 442 2314375; fax: +90 442 2360948. E-mail addresses: [email protected], [email protected] _ Gu¨lc¸in). (I. Peer review under responsibility of King Saud University.
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Carbonic anhydrase (CA: EC 4.2.1.1.) is a metalloenzyme containing a Zn2+ ion. CA is a very important enzyme, which regulates CO2 levels in living organisms. CA was first isolated from mammalian erythrocyte (Gu¨lc¸in et al., 2004; Gu¨ney et al., 2014). It was reported that CA was isolated, purified and characterized from many different plant and animal tissues (Gu¨lc¸in et al., 2004; Topal and Gu¨lc¸in, 2014). All these enzymes catalyze the reactions as shown below: þ CO2 þ H2 O H2 CO3 HCO 3 þH
http://dx.doi.org/10.1016/j.arabjc.2014.08.005 1878-5352 ª 2014 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
2
H. Go¨cer et al.
CA has active properties in the kidney, gastric mucosa, eye lens, salivary glands, brain, nerve myelin sheath, pancreas, prostate and uterus (Gu¨lc¸in and Beydemir, 2013; Arabaci et al., 2014). CA isoforms participate in several important biological processes and they are found in a variety of tissues. Studies demonstrated important roles of CAs in a variety of physiological procedures, and showed that extraordinary levels or activities of these enzymes have been often related with different human diseases (Innocenti et al., 2010a; Go¨c¸er et al, 2014). CA inhibitors (CAIs) are classified into two main groups, the metal complexing anions and the unsubstituted sulfonamides. Sulfonamides are very important CAIs. Anions may bind either in a tetrahedral geometry with the metal ions or as a trigonal-bipyramidal adduct. Sulfonamides bind in a tetrahedral geometry with the Zn2+ ions (Bertini et al., 1982; Lindahl et al., 1990; Briganti et al., 1996; Supuran and Scozzafava, 2000; Kim et al., 2000). E Zn2þ OH2 þ I $ E Zn2þ I þ H2 O E Zn2þ OH2 þ I $ E Zn2þ H2 OðIÞ The discovery of CA inhibition with sulfanilamide by Mann and Keilin (1940) was the beginning of many scientific discoveries and applications. Important drugs, such as antihypertensives of benzothiadiazine and high-ceiling diuretics were prepared following the discovery (Maren, 1967). More than 100 sulfonamides were investigated by means of kinetic, physiological and pharmacological studies. Following these, many studies were performed for preparing aromatic sulfonamides, which were investigated for their CA inhibitory action. Among the aromatic sulfonamides, benzene sulfonamides have shown the best CA inhibitory action (Supuran et al., 2004). Over the years many different sulfonamides have been reported to act as CAIs. One of the most investigated compounds is phenol (Go¨ksu et al., 2014). After many studies, excellent results have been achieved, especially associated with sulfonamides and their derivatives. In 1982 Lindskog’s group reported that phenols act as competitive inhibitors against human cytosolic CA II (Tibell et al., 1985; Simonsson et al., 1982). Also, extra structural description on the binding mode of phenolic compounds or derivatives to the CA active site has been clarified (Supuran and Scozzafava 2002). In this context, we aimed to extend our study on the CA inhibitory properties of some phenolic sulfonamides. Table 1
2. Result and discussion 2.1. CA purification and activity assay In this study, hCA I, and II isoenzymes were purified separately from human fresh erythrocytes, using a simple one-step chromatographic method using Sepharose-4B-L-tyrosine-sulfanilamide column material. In the first part of our study, we have identified the inhibitory effects of phenolic sulfonamides 1–4 on the esterase activity of both isoenzymes (Table 1). In one of our early studies we have reported the synthesis, acetylcholinesterase inhibitory and antioxidant activity of compounds 1–4 (Go¨c¸er et al., 2013). The inhibition measurements were performed with esterase activity methods described by Akincioglu et al. (2013a,b). The base of this method is based on the destruction of CA ester bonds. In this process, the CA enzyme hydrolyzes the phenyl acetate and the resulting product showed absorption at 348 nm. In our study, this method was preferred due to its high sensitivity compared to methods of Wilbur and Anderson (1948). 2.2. CA isoenzymes inhibitory effects CAIs have been essentially used as diuretics and antiglaucoma agents (Winum et al., 2006; Supuran 2007, 2008; De Simone et al, 2008; Hen et al., 2011). In recent studies for the synthesis of CAIs, the sulfonamide compounds (R-SO2NH2) are very important and widely used in zinc binding functions (Akıncıog˘lu et al., 2013a; Akbaba et al., 2013a; C¸etinkaya et al., 2013; Aksu et al., 2013). They are designed and synthesized according to these characteristics. We firstly reported the study on the inhibitory effects of synthesized novel sulfonamides 1–4 and on the esterase activity of hCA I, and II. In this study inhibitory effects of compounds on the CA isoenzymes were investigated. Results were determined for hCA I, and II by drawing Lineweaver-Burk graphs (1934). After hCA I, and II inhibitory effects of the novel phenolic sulfonamides 1–4 the IC50 and average Ki values were calculated. The results given in Table 2 show the following regarding the inhibitory effects of hCA I, and II by novel phenolic sulfonamides 1–4. CA isoenzyme inhibitors block the active site of CA isoenzymes and in this way the actual metabolism of the substrate is inhibited and the body functions remain normal (Shahwar et al., 2012). In the current study, we demonstrated strong
The chemical structure of phenolic sulfonamides 1–4. Compounds
R1
R2
R3
R4
R5
1
OH
H
H
H
H
2 3 4
H H OH
OH OH OH
OH H H
H OH H
H H H
O
R1 H N
R2
S
CH3
O R3
R5 R4
Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
Sulfonamides inhibit carbonic anhydrase
3
Table 2 Human carbonic anhydrase isoenzyme (hCA I and hCA II) inhibition value with some phenolic sulfonamide derivatives (1–4) by an esterase assay with 4-nitrophenylacetate as substrate. Compounds
1 2 3 4
IC50 (lM)
KI (lM)
hCA I
R2
hCA II
R2
hCA I
hCA II
3.55 3.60 3.43 5.41
0.997 0.995 0.961 0.985
2.94 2.42 3.43 4.07
0.985 0.989 0.9632 0.994
0.827 ± 0.096 2.508 ± 0.099 1.884 ± 0.098 1.592 ± 0.033
0.745 ± 0.173 0.919 ± 0.019 0.867 ± 0.034 1.046 ± 0.008
inhibitory effects of newly synthesized phenolic sulfonamide compounds (1–4) on both cytosolic isoenzymes. The arithmetic average Ki values of sulfonamides compounds (14) are in the range of 0.827–2.508 lM for hCA I, and 0.745–1.046 lM for hCA II (Table 2). Half-maximum inhibitory concentration (IC50) measures the effectiveness of novel phenolic sulfonamides 1–4 in inhibiting CA isoenzyme function. Lower IC50 and Ki values show strong CA isoenzyme inhibitory effects of sulfonamides. These data are very important for biologically active compounds. In the last years, a lot of sulfonamide drug groups have been developed in the drug markets (Supuran and Scozzafava 2000). At first, Lindskog’s group (Simonsson et al., 1982) reported phenols as inhibitors against human CA II and extra structural definition on the binding mode of phenolic derivatives to the CA active site was obtained (Supuran and Scozzafava 2002). CA inhibitory effects of a large spectrum of phenolic compounds including melatonin (Beydemir and Gu¨lc¸in, 2004), morphine (C¸oban et al., 2007), vitamin E (ArasHisar et al., 2004), caffeic acid phenethyl ester (Go¨c¸er and Gu¨lc¸in, 2013), a series of antioxidant phenols (Sentu¨rk et al., 2009), a series of phenolic acids (Ozturk Sarikaya et al., 2010), a series of natural product polyphenols and phenolic acids (Innocenti et al., 2010a,b), two different series of natural phenolic compounds (Sentu¨rk et al., 2011; Ozturk Sarikaya et al., 2011; Gu¨lc¸in and Beydemir, 2013), antioxidant polyphenol natural products (Innocenti et al., 2010b), (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives (Nar et al., 2013), natural and synthetic bromophenols (Akbaba et al. 2013b; Balaydın et al. 2012a,b), novel phenolic sulfonamides (Akıncıog˘lu et al., 2013b), novel sulfonamide derivatives of aminoindanes and aminotetralins (Akbaba et al., 2013b), novel phenolic benzylamine derivatives (C¸etinkaya et al., 2013), sulfonamide analogs of dopamine related compounds (Aksu et al., 2013), new benzotropons (Gu¨ney et al., 2014) and novel sulfonamides incorporating tetralin scaffold (Akıncıog˘lu et al., 2013b) have been reported. These extensive studies indicate the importance of CA enzyme inhibitors. The results obtained from Table 2 clearly show that the physiologically dominant cytosolic isozymes hCA I, and II were effectively inhibited by sulfonamide compounds 1–4. The reason for this is that both cytosolic isoenzymes have a high sequence of amino acid homology within their active sites (Xue et al., 1993; Brzozowski et al., 2012). Sulfonamides 1–4 have one aromatic ring and –OH groups. Here, compounds 1–4 have been studied as hCA isoenzymes inhibitors. The logic of working these sulfonamides as potent CA inhibitors exists in the fact that the compounds with aromatic rings have been identified to be the inhibitor with CO2 as the substrate for the main isoform of CA.
3. Conclusion In conclusion, acetylcholine esterase inhibitors and antioxidant sulfonamides 1–4 were evaluated for CA inhibitory properties. In this study, micromolar levels of Ki and IC50 values were observed. We show by this study that compounds 1–4 are both selective cytosolic CA isoenzyme inhibitors with selectivity ratios in the range of 0.745–2.508 lM. These results clearly indicate that phenolic sulfonamides 1–4 may be used as leads for generating both powerful cytosolic CA inhibitors eventually targeting other isoforms. 4. Experimental 4.1. General information The chemicals and solvents used in this study are commercially available. All solvents were purified according to standard procedures. CA inhibitory properties of samples were determined using a spectrophotometer (UV-1208, Shimadzu, Japan). Compounds 1–4 were synthesized according to our previous procedure (Go¨c¸er et al., 2013). 4.2. Purification of CA isoenzymes CA isoenzymes were purified via a simple single-step method Sepharose-4B-L-tyrosine-sulfanilamide affinity gel chromatography (Atasaver et al., 2013), as defined previously (Ozturk Sarikaya et al., 2010; Sentu¨rk et al., 2011). Fresh human erythrocyte samples were centrifuged at 10,000g for 30 min and then removed and the serum isolated. The pH was adjusted to 8.7 with solid Tris. Sepharose-4B-L-tyrosine-sulfanilamide affinity column equilibrated with Tris–HCl (25 mM)/Na2SO4 (0.1 M; pH 8.7). The Sepharose-4B-L-tyrosine-sulfanilamide affinity gel was washed with Tris–HCl (25 mM)/Na2SO4 (22 mM) at pH 8.7. Both CA isozymes were eluted with NaCl (1.0 M)/Na2 HPO4 (25 m) at pH 6.3 and NaCH3COO (0.1 M)/NaClO4 (0.5 M) at pH 5.6, respectively. During both isozymes purification procedures, proteins stream was monitored at 280 nm (Beydemir and Gu¨lc¸in 2004; Go¨c¸er and Gu¨lc¸in, 2013). 4.3. Esterase activity assay and protein determination A spectrophotometric method (SHIMADZU, UVmini-1240 UV–VIS Spectrophotometer) was used for the determination of carbonic anhydrase activities (Verpoorte et al. 1967). This method was previously described (Hisar et al., 2005a; Gu¨lc¸in and Beydemir, 2013). The change in absorbance at 348 nm of 4-nitrophenylacetate (NPA) to 4-nitrophenylate was recorded
Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005
4 for 3 min at 25 C. The control medium contained 1.4 mL TrisSO4 buffer (0.05 M, pH 7.4), 4-nitrophenylacetate (1 mL, 3 mM), H2O (0.5 mL) and enzyme solution (0.1 mL). Final volume reached 3.0 mL. The control was obtained by preparing the mixture without the enzyme solution. All measurements were recorded as triplicate. The Ki values were determined from a series of experiments using three different phenolic sulfonamide compound (1–4) concentrations and NPA as the substrate at five different concentrations for the construction of Lineweaver-Burk curves (1934) described previously (Hisar et al., 2005b; Sentu¨rk et al., 2008). Furthermore the quantity of protein during every purification step was determined spectrophotometrically at 595 nm according to the Bradford method (1976). As in other studies, bovine serum albumin was used as standard protein in this study (Gu¨lc¸in et al., 2005). 4.4. SDS–polyacrylamide gel electrophoresis The purity of the enzymes was confirmed using SDS–polyacrylamide gel electrophoresis (SDS–PAGE). The running and stacking gels contained 10% and 3% acrylamide, respectively, and 0.1% SDS, according to the Laemmli procedure (1970) described previously (Sisßeciog˘lu et al., 2009, 2010). To each electrophoresis medium a 20 mg sample aliquot was applied. SDS–polyacrylamide gel was painted with Coomassie brilliant blue R-250 reagent over night. Then, the electrophoretic zymogram was photographed (Ko¨ksal et al., 2012). Acknowledgments The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at the King Saud University for funding this research through the Research Group Project no. RGP-VPP-254. References _ Akbaba, Y., Akıncıog˘lu, A., Go¨c¸er, H., Go¨ksu, S., Gu¨lc¸in, I., Supuran, C.T., 2013a. Carbonic anhydrase inhibitory properties of novel sulfonamide derivatives of aminoindanes and aminotetralins. J. Enzyme Inhib. Med. Chem. 29, 35–42. Akbaba, Y., Balaydın, H.T., Menzek, A., Go¨ksu, S., S ß ahin, E., Ekinci, D., 2013b. Synthesis and biological evaluation of novel bromophenol derivatives as carbonic anhydrase inhibitors. Arch. Pharm. 346, 447–454. _ Akıncıog˘lu, A., Akbaba, Y., Go¨c¸er, H., Go¨ksu, S., Gu¨lc¸in, I., Supuran, C.T., 2013a. Novel sulfamides as potential carbonic anhydrase isoenzymes inhibitors. Bioorg. Med. Chem. 21, 379– 1385. _ Go¨ksu, S., 2013b. Novel Akıncıog˘lu, A., Topal, M., Gu¨lc¸in, I., sulfamides and sulfonamides incorporating tetralin scaffold as carbonic anhydrase and acetylcholine esterase inhibitors. Arch. Pharm. 347, 68–76. _ Go¨ksu, S., Tu¨mer, Aksu, K., Nar, M., Tanc¸, M., Vullo, D., Gu¨lc¸in, I., F., Supuran, C.T., 2013. The synthesis of sulfamide analogues of dopamine related compounds and their carbonic anhydrase inhibitory properties. Bioorg. Med. Chem. 21, 2925–2931. _ Alwasel, S., 2014. Capsaicin: a potent inhibitor Arabaci, B., Gu¨lc¸in, I., of carbonic anhydrase isoenzymes Molecules 19, 10103–10114. _ Yanık, T., 2004. ArasHisar, S ß ., Hisar, O., Beydemir, S ß ., Gu¨lc¸in, I., Effect of vitamin E on carbonic anhydrase enzyme activity in rainbow trout (Oncorhynchus mykiss) erythrocytes in vitro and in vivo. Acta Vet. Hung. 52, 413–422.
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Please cite this article in press as: Go¨cer, H. et al., Carbonic anhydrase inhibitory properties of phenolic sulfonamides derived from dopamine related compounds. Arabian Journal of Chemistry (2014), http://dx.doi.org/10.1016/j.arabjc.2014.08.005