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! 2014 Informa UK Ltd. DOI: 10.3109/14756366.2014.956310

Carbonic anhydrase inhibitors: guaiacol and catechol derivatives effectively inhibit certain human carbonic anhydrase isoenzymes (hCA I, II, IX and XII) Andrea Scozzafava1, Maurizio Passaponti1, Claudiu T. Supuran1,2, and _Ilhami Gu¨lc¸in3,4 1

Dipartimento di Chimica Ugo Schiff, Universita` degli Studi di Firenze, Florence, Italy, 2Section of Pharmaceutical and Nutriceutical Sciences, Neurofarba Department, Universita` degli Studi di Firenze, Florence, Italy, 3Chemistry Department, Science Faculty, Ataturk University, Erzurum, Turkey, and 4Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia

Abstract

Keywords

Carbonic anhydrases (CAs) are widespread metalloenzymes in higher vertebrates including humans. A series of phenolic compounds, including guaiacol, 4-methylguaiacol, 4-propylguaiacol, eugenol, isoeugenol, vanillin, syringaldehyde, catechol, 3-methyl catechol, 4-methyl catechol and 3-methoxy catechol were investigated for their inhibition of all the catalytically active mammalian isozymes of the Zn2+-containing CA (EC 4.2.1.1). All the phenolic compounds effectively inhibited human carbonic anhydrase isoenzymes (hCA I, II, IX and XII), with Kis in the range of 2.20–515.98 lM. The various isozymes showed diverse inhibition profiles. Among the tested phenolic derivatives, compounds 4-methyl catechol and 3-methoxy catechol showed potent activity as inhibitors of the tumour-associated transmembrane isoforms (hCA IX and XII) in the submicromolar range, with high selectivity. The results obtained from this research may lead to the design of more effective carbonic anhydrase isoenzyme inhibitors (CAIs) based on such phenolic compound scaffolds.

Carbonic anhydrases, catechol derivatives, enzyme inhibition, guaiacol derivatives, isoenzymes

Introduction Carbonic anhydrase (CA; EC 4.2.1.1) catalyses the simple but crucial reaction between carbon dioxide (CO2) and water, leading 1–4 . to the formation of protons (H+) and bicarbonate (HCO 3) These enzymes are common to all organisms, from the very simple to complex. This metalloenzyme family is involved in numerous pathological and physiological processes in a different tissues and organs, including biosynthetic reactions, such as gluconeogenesis, lipid and urea synthesis, calcification, lipogenesis, ureagenesis, tumorigenicity, and the growth and virulence of various pathogens1,3. Furthermore, five distinct genetic families, the a-, b-, c-, dand z-CAs, are known to date, which constitute an interesting example of convergent evolution at the molecular level5–11. These five CA families vary in their preference for the catalytic metal ions used within the active site: for performing the catalysis: Zn2+ ions are used by the above-mentioned five CA classes, whereas c-CAs most likely utilize Fe2+enzymes12–14. As the a-isoforms of CA differ in location and tissue distribution, cytosolic (CA I, II, III, VII and XIII), membrane-bound (CA IV, IX, XII and XIV),

Address for Correspondence: Claudiu T. Supuran, Dipartimento di Chimica Ugo Schiff, Universita` degli Studi di Firenze, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy. Tel: +39-0554573005. Fax: +39-055-4573385. E-mail: [email protected] _ Ilhami Gu¨lc¸in, Chemistry Department, Science Faculty, Ataturk University, Erzurum 25240, Turkey. Tel: +90-442-2314375; Fax: +90442-2314109. E-mail: [email protected]

History Received 4 August 2014 Accepted 16 August 2014 Published online 4 November 2014

mitochondrial (CA VA and VB) and secreted (CA VI) forms have been described1,15,16. The CA IX and XII isoenzymes are known as the membrane CAs associated with cancers and have also been found in a very limited number of normal tissues, such as gastrointestinal mucosa and related structures1,17,18. CA inhibitors (CAIs) are clinically used as antiglaucoma drugs and diuretics. Additionally, it has lately emerged that CAIs could have potential as anticancer, anti-obesity and anti-infective drugs. Most often, CAIs have been investigated with the classical CA inhibitors belonging to the sulphonamide/sulphamates class, but other chemo-types have also been explored, such as boronic acids, metal-complexing anions and similar small molecules, and phenols1,19–24. These sulphonamides are clinically used, as antiglaucoma agents, and also for the therapy of other diseases, such as increased intracranial pressure, neuromuscular pathologies and various neurological disorders, such as epilepsy, hypokalaemia, tardive dyskinesia, genetic hemiplegic migraine and ataxia, essential tremor and Parkinsons disease, and mountain sickness. For this reason, some chemical compounds and drugs of this pharmacological class are under research and constant development25,26. Phenolic compounds incorporate a hydroxyl group bonded directly to an aromatic hydrocarbon atom27–30, with the number and position of –OH groups on the aromatic ring creating variety. Methoxyphenols have a low-molecular weight and are semivolatile polar aromatic compounds31. Guaiacol (2-methoxyphenol) has been extensively used as a lignin model compound because guaiacol-type compounds with their two oxygen-containing functional groups, such as a hydroxyl group (–OH) and methoxy group (–OCH3), provide

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Figure 1. Chemical structures of the phenolic compounds (1–11) were studied for their inhibition parameters of cytosolic isoforms hCA I and II and transmembrane tumourassociated isoforms of hCA IX and XII.

bioability32,33. Guaiacol is produced through the non-oxidative decarboxylation of vanillic acid, the oxidation product of vanillin, a derivative of ferulic acid34. Many recent studies are dedicated to the investigation of the properties of guaiacol35–37 and it has been shown that the phenolic aromatic C–O bond is stronger than that the O–CH3 bond of the guaiacol methoxy group37. Therefore, its cleavage requires more severe conditions, such as high temperature and high pressure38. Guaiacol, an active component isolated from some higher plants, has been demonstrated to have significant antioxidant, antibacterial and anti-inflammatory activities, and has been clinically used for the treatment of respiratory diseases39. Catechol, which is found as a constituent of edible plants, may undergo oxidative metabolism to electrophilic o-quinones by the Cytochrome P450 enzyme system and peroxidase40. Catechol is used as precursor for the production of pharmaceuticals and is an important chemical in food applications, being extensively used in the manufacture of synthetic flavours, such as vanillin by the food industry41. The first commercial synthesis of vanillin began with the more readily available natural antioxidant compound eugenol; today, artificial vanillin is derived from guaiacol42. Catechol is also produced by some microorganisms39,43. In particular, many studies have recently focused on the biological activities of catechol and its derivatives, such as 3-methylcatechol and 4-methyl catechol44–46. It has been inferred that the reactivity of guaiacol tends to be enhanced by increasing the number of substituent groups on the benzene rings. Because the enhancing effect of an –OH group was more obvious than that of –CH3, catechol is more reactive than cresol. As a result, the substituent groups of the benzene ring in guaiacol compounds have important influences on their derivatives47. In earlier studies, we investigated CA inhibition by a number of phenols and their derivatives48–51. Here, we continue these previous studies with the main goal being to determine the effect of certain guaiacol and catechol derivatives on the inhibition of various CA isoenzymes.

Results and discussion Phenols are very active compounds for quenching reactive oxygen species and are reported to possess antioxidant52–55 and other anticancer, antimutagenic, anticarcinogenic, antiviral, antibacterial and anti-inflammatory activities56–58. Phenolic compounds and polyphenols possess unrelated scaffolds but strong antioxidant properties50,51. The chemical structures of the phenolic compounds (1–11) are illustrated in Figure 1. Sulphonamide and sulphamates, as classical CAIs, have long been used clinically as diuretics and antiglaucoma drugs19,59–62. In addition, these CAIs exhibit potential anticancer, anticonvulsant, anti-infective, antipain and antiobesity effects. The design of CAIs as therapeutic agents is related to the large number of isoforms in humans, their rather diffuse localization in many tissues or organs, and the lack of isozyme selectivity of the currently available inhibitors of sulphonamide or sulphamates types19,50,59–61,63–66. Indeed, among the sulphonamide derivatives in clinical applications, there are no compounds that selectively inhibit some CA isoforms with therapeutic value1. Based on the studies of CAIs with marked inhibition activity and considering the literature on phenolic compounds as CAIs1,67–69, phenols as well as phenolic derivatives constitute interesting clues for identifying novel CAIs. Here, we report the inhibition profile of the four catalytically active hCA isoforms (hCA I, II, IX and XII) with a series of phenolic derivatives (1–11) derived from guaiacol and catechol. These derivatives possess between 2 and 4 phenolic moieties in scaffolds, which are quite variable and typical of phenolic compounds. We discovered micromolar inhibition of the four hCA isoforms (hCA I, II, IX and XII). The common denominator of all used phenolic derivatives (1–11) is the fact that they incorporate phenolic moieties. It was reported that phenolic compounds act as CAIs62,67,70,71 by binding to CA in a diverse manner compared to the classical CAIs, which coordinate the Zn2+ ion in the active site of the enzyme by substituting a water molecule or hydroxide ion for the

Carbonic anhydrase inhibitors

DOI: 10.3109/14756366.2014.956310

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Table 1. Inhibition constants of certain phenolic compounds derived from guaiacol and catechol against four human carbonic anhydrase isoenzymes (hCA I, II, IX and XII) using an esterase bioassay. Ki (lM) Compounds

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1 2 3 4 5 6 7 8 9 10 11

R1

R2

R3

Name

H H H H H H OCH3

H CH3 CH2–CH2–CH3 CH2–CH2 ¼ CH2 CH ¼ CH–CH3 CHO CHO

– – – – – – –

Guaiacol 4-Methylguaiacol 4-Prophylguaiacol Eugenol Isoeugenol Vanillin Syringaldehyde

OH OH OH OH

H CH3 H OCH3

H H CH3 H

Catechol 3-Methyl catechol 4-Methyl catechol 3-Methoxy catechol

fourth, non-protein ligand67,72. X-ray crystallography studies from Christianson’s group showed the inhibitor to be anchored by means of its –OH moiety to the fourth Zn2+ ligand by means of a hydrogen bond. A second hydrogen bond has been evidenced between the oxygen atom of phenol and the amide NH of Thr199, an amino acid residue conserved in all a-CAs1,19,73. In this study, the CA inhibitory ability of all phenolic compounds (1–11) was measured against the cytosolic isoforms hCA I and II as well as the membrane-associated isoforms hCA IX and XII using the stopped flow assay method, and the results are displayed in Table 1. Following should be noted regarding the inhibition of these hCA isozymes with phenols 1–11. All compounds exhibited a marked inhibitory activity against cytosolic isoenzyme hCA I with Ki values from the lowmicromolar range of 5.95–10.81 lM, except for catechol (Table 1). The hCA I is highly abundant in red blood cells and is found in many tissues. The weakest inhibition was observed for catechol with Ki value of 247.50 lM. Among these phenol derivatives (1–11), the most active compound against hCA I was 3-methyl catechol (9) possessing orto-CH3 phenolic moiety, with a Ki value of 5.95 lM. It has been reported that phenolics are not biologically active unless substitution at either the ortho- or para-position has increased the electron density at the –OH group and lowered the oxygen–hydrogen bond energy. Steric and electronic effects are responsible for biological activity30,74,75. With regard to the profiling assay against hCA II, all the tested phenolic compounds (1–11) were active, with Ki values in the range of 2.20–8.51 mM. The results clearly showed that 4-methyl catechol (10) and 3-methoxy catechol (11) are the most suitable inhibitors for cytosolic isoenzymes hCA II, with Ki values of 2.20 and 2.76 mM, respectively. The schematic representation of the proposed interaction between guaiacol (1) and the active site region of hCA II is presented in Figure 2. In guaiacol, a hydroxyl group (–OH) is bonded to a 1-methoxy benzene ring in an orthoposition. It was reported that para-position is favour of biological activity30,74,75. Many studies have demonstrated that the inhibition of CA II is due to the ability of an inhibitor to mimic the tetrahedral transition state when binding to the catalytic Zn2+ located in the active site1,4,19,71. The physiologically dominant cytosolic isoform hCA II is ubiquitous and is being involved in several diseases, such as epilepsy, edema, glaucoma and altitude sickness76.

hCA I

hCA II

hCA XII

7.50 9.15 10.34 8.32 10.29 11.37 10.92

5.63 7.74 8.51 7.27 6.73 7.15 6.68

9.98 9.89 9.01 9.62 9.32 9.81 9.11

9.83 8.55 9.12 8.89 9.13 8.39 7.70

247.50 5.95 6.16 6.32

5.51 4.69 2.76 2.20

373.23 9.55 8.11 7.83

515.98 7.22 6.58 7.53

Leu198

Val143

Trp209

OCH3 NH

hCA IX

O

Val121

H O

Thr 199

O

H

2+Zn

H His94

His119 His96

Figure 2. Schematic representation of the proposed interaction between guaiacol (1) and the active site region of hCA II.

To date, 16 isoforms of human carbonic anhydrase (hCA) have been discovered; among them, the transmembrane tumourassociated isoforms (hCA IX and hCA XII) are overexpressed in several types of tumours. Many sulphonamide derivatives have been investigated for their CA inhibition activity in the search for selective hCA IX and hCA XII inhibitors, because their lack of selectivity is the major challenge for the wide use of chemotherapeutic agents in cancer therapy1,77–84. Regarding the hCA IX isozyme, the tested phenolic compounds (1–11) showed high-inhibitory activities with inhibition constants from 7.83 to 9.98 mM, except for catechol, which showed a Ki value of 373.23 mM. As observed in the inhibition profiles of hCA I, IX and XII, catechol was less effective against these isoenzymes. Moreover, as with hCA II, 3-methoxy catechol was the most potent hCA IX inhibitor, with a Ki value of 7.83 mM. hCA IX is expressed in many tumours, with the overall consequence that an imbalance in pH is increased in the tissue. In contrast to normal tissues (pH 7.4), most hypoxic tumours are acidic (pH 6.0). Pastorekova’s group reported that the role of hCA IX was related to the acidification processes in hypoxic tumours15. This isoenzyme is a catalytically active

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plasma membrane isoform of CA that normally controls the differentiation of gastric mucosa. Its abnormal expression is strongly associated with tumours, and it is often regulated by hypoxia. Indeed, the expression level of hCA IX was elevated in response to hypoxia, which is a consequence of the rapid growth of many tumours. The general result of hCA IX overexpression in tumours is a pH decrease in the extracellular micro-environment from pH 7.4 (normal tissue) to 6.8 (hypoxic tumour), which promotes tumour cell survival and invasion2,85. Considering the abnormally high-expression of CA IX in many hypoxic tumours and its demonstrated role in the tumour acidification processes and oncogenesis, this isoform constitutes an attractive target for anticancer therapy86. Finally, potent inhibition was exhibited by 10 of the 11 phenolic compounds (1–11) against the transmembrane, tumourassociated isozyme hCA XII. Both transmembrane and tumourassociated isozymes, i.e. hCA IX and XII, were also effectively inhibited by phenolic compounds 1–11, with Ki values in the range of 7.83–9.98 mM against the hCA IX and of 6.58–9.83 mM against the hCA XII except for catechol, which showed a less effective inhibition profile against both transmembrane and tumour-associated isoform hCA IX and hCA XII. The Ki values for catechol were 373.23 and 515.98 mM against the hCA IX and hCA XII isozymes, respectively. The results showed that inhibition profile of phenolic compounds 1–11 for the transmembrane, tumour-associated isoform hCA IX was rather similar to that for another transmembrane, tumour-associated isoform hCA XII. It has been reported that the biological activity of phenolics depends on the number and position of the –OH groups bound to the aromatic ring, the binding site and mutual position of –OH in the aromatic ring and the type of substituents16,29,86–89.

Conclusion To explore the prospective mechanism of action and assessment of their in vitro CA inhibitory capacity against hCA I, II, IX and XII, phenols derivatives (1–11) were evaluated. All of these phenol derivatives (1–11) effectively inhibited these isoenzymes, with Ki values in the range of 2.20–515.98 lM. The various isozymes showed diverse inhibition profiles. These data may explain the beneficial health effects of some of these compounds and may lead to drug design campaigns for more effective CAIs.

hCA Isoenzymes Inhibition Assay An applied photophysics stopped flow instrument was used to assay the catalytic/inhibition of various CA isozymes, as reported by Khalifah90. Phenol red (20 mM) was used as an indicator, with an absorbance maximum of 557 nm, with HEPES (10 mM, pH 7.4) as a buffer and 0.1 M Na2SO4 or NaClO4 (for maintaining constant ionic strength; these anions are not inhibitory at the used concentration). The CA-catalysed CO2 hydration was followed for a period of 10–100 s. For the determination of the kinetic parameters and inhibition constants, the saturated CO2 concentrations ranged from 1.7 to 17 mM. For each inhibitor, at least six traces of the initial 5–10% of the reaction were used for determining the initial velocity. The uncatalysed rates were determined in the same manner and subtracted from the total observed rates. Stock solutions of inhibitor (10 mM) were prepared in distilled–deionized water, and dilutions up to 0.01 lM were performed with distilled–deionized water. Inhibitor and enzyme solutions were preincubated together for 15 min at room temperature prior to the assay to allow for the formation of the E–I complex. The inhibition constants were obtained by non-linear least-squares methods using PRISM 3, as reported earlier, and represent the mean from at least three

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different determinations. Human CA isozymes were prepared in recombinant form as reported earlier by our group51,62,91.

Declaration of interest The authors declared that there is no conflict of interest. This work was financed in part by two EU projects of the 7th FP, Metoxia and Dynano. IG would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project no RGP-VPP-254.

References 1. Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nat Rev Drug Disc 2008;7:168–81. 2. Capasso C, Supuran CT. Sulfa and trimethoprim-like drugsantimetabolites acting as carbonic anhydrase, dihydropteroate synthase and dihydrofolate reductase inhibitors. J Enzyme Inhib Med Chem 2014;29:379–87. 3. Supuran CT. Structure-based drug discovery of carbonic anhydrase inhibitors. J Enzyme Inhib Med Chem 2012;27:759–72. 4. Gu¨ney M, Co¸skun A, Topal F, et al. Oxidation of cyanobenzocycloheptatrienes: synthesis, photooxygenation reaction and carbonic anhydrase isoenzymes inhibition properties of some new benzotropone derivatives. Bioorg Med Chem 2014;22:3537–43. 5. Said HM, Hagemann C, Carta F, et al. Hypoxia induced CA9 inhibitory targeting by two different sulfonamide derivatives including acetazolamide in human Glioblastoma. Bioorg Med Chem 2013;21:3949–57. 6. Alterio V, Di Fiore A, D’Ambrosio K, et al. Multiple binding modes of inhibitors to carbonic anhydrases: how to design specific drugs targeting 15 different isoforms? Chem Rev 2012;112:4421–68. 7. Monti SM, Supuran CT, De Simone G. Anticancer carbonic anhydrase inhibitors: a patent review (2008–2013). Expert Opin Ther Pat 2013;23:737–49. 8. Supuran CT. Carbonic anhydrase inhibitors. Bioorg Med Chem Lett 2010;20:3467–74. 9. Rummer JL, McKenzie DJ, Innocenti A, et al. Root effect hemoglobin may have evolved to enhance general tissue oxygen delivery. Science 2013;340:1327–9. 10. Nishimori I, Vullo D, Minakuchi T, et al. Sulfonamide inhibition studies of two b-carbonic anhydrases from the bacterial pathogen Legionella pneumophila. Bioorg Med Chem 2014;22:2939–46. _ Menzek A. Synthesis and carbonic 11. C¸etinkaya Y, Go¨c¸er H, Gu¨lc¸in I, anhydrase isoenzymes inhibitory effects of brominated diphenylmethanone and its derivatives. Arch Pharm 2014;347:354–9. 12. Smith KS, Jakubzick C, Whittam TS, Ferry JG. Carbonic anhydrase is an ancient enzyme widespread in prokaryotes. Proc Natl Acad Sci USA 1999;96:15184–9. 13. De Simone G, Alterio V, Supuran CT. Exploiting the hydrophobic and hydrophilic binding sites for designing carbonic anhydrase inhibitors. Expert Opin Drug Discov 2013;8:793–810. _ Go¨ksu S. Novel sulfamides and 14. Akıncıog˘lu A, Topal M, Gu¨lc¸in I, sulfonamides incorporating tetralin scaffold as carbonic anhydrase and acetylcholine esterase inhibitors. Arch Pharm 2014;347:68–76. 15. Pastorekova S, Parkkila S, Pastorek J, Supuran CT. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J Enzyme Inhib Med Chem 2004;19:199–229. _ Caffeic acid phenethyl ester (CAPE): a potent 16. Go¨c¸er H, Gu¨lc¸in I. carbonic anhydrase isoenzymes inhibitor. Int J Acad Res 2013;5: 150–5. 17. Durdagi S, Scozzafava G, Vullo D, et al. Inhibition of mammalian carbonic anhydrases I–XIV with grayanotoxin III: solution and in silico studies. J Enzyme Inhib Med Chem 2014;29:469–75. 18. Bilginer S, Unluer E, Gul HI, et al. Carbonic anhydrase inhibitors. Phenols incorporating 2- or 3-pyridyl-ethenylcarbonyl and tertiary amine moieties strongly inhibit Saccharomyces cerevisiae b-carbonic anhydrase. J Enzyme Inhib Med Chem 2014;29:495–9. 19. Supuran CT, Scozzafava A, Casini A. Carbonic anhydrase inhibitors. Med Res Rev 2003;23:146–89. 20. Sharma A, Tiwari M, Supuran CT. Novel coumarins and benzocoumarins acting as isoform-selective inhibitors against the tumor-associated carbonic anhydrase IX. J Enzyme Inhib Med Chem 2014;29:292–6.

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21. Pan J, Lau J, Mesak F, et al. Synthesis and evaluation of 18F-labeled carbonic anhydrase IX inhibitors for imaging with positron emission tomography. J Enzyme Inhib Med Chem 2014;29:249–55. 22. Joseph P, Turtaut F, Ouahrani-Bettache S, et al. Cloning, Characterization, and inhibition studies of a b-carbonic anhydrase from Brucella suis. J Med Chem 2010;53:2277–85. 23. Burghout P, Vullo D, Scozzafava A, et al. Inhibition of the b-carbonic anhydrase from Streptococcus pneumoniae by inorganic anions and small molecules: toward innovative drug design of antiinfectives? Bioorg Med Chem 2011;19:243–8. 24. Aksu K, Nar M, Tanc¸ M, et al. The synthesis of sulfamide analogues of dopamine related compounds and their carbonic anhydrase inhibitory properties. Bioorg Med Chem 2013;21:2925–31. _ Rosmarinic acid: a potent carbonic anhydrase 25. Topal M, Gu¨lc¸in I. isoenzymes inhibitor. Turk J Chem 2014;38:894–902. _ Synthesis and carbonic 26. C¸etinkaya Y, Go¨c¸er H, Go¨ksu S, Gu¨lc¸in I. anhydrase isoenzymes inhibitory effects of novel benzylamine derivatives. J Enzyme Inhib Med Chem 2014;29:168–74. 27. Robbins RJ. Phenolic acids in foods: an overview of analytical methodology. J Agric Food Chem 2003;51:2866–87. _ Antioxidant activity of eugenol – a structure and activity 28. Gu¨lc¸in I. relationship study. J Med Food 2011;14:975–85. _ Antioxidant activity of food constituents – an overview. 29. Gu¨lc¸in I. Arch Toxicol 2012;86:345–96. _ Beydemir S. Phenolic compounds as antioxidants: carbonic 30. Gu¨lc¸in I, anhydrase isoenzymes inhibitors. Mini Rev Med Chem 2013;13: 408–30. 31. Lauraguaisa A, Coeur-Tourneur C, Cassez A, et al. Atmospheric reactivity of hydroxyl radicals with guaiacol (2-methoxyphenol), a biomass burning emitted compound: secondary organic aerosol formation and gas-phase oxidation products. Atmos Environ 2014; 86:155–63. 32. Mohan D, Pittman CU, Steele PH. Pyrolysis of wood/biomass for bio-oil: a critical review. Energy Fuels 2006;20:848–89. 33. Elliott DC, Hart TR. Catalytic hydroprocessing of chemical models for bio-oil. Energy Fuels 2009;23:631–7. 34. Chang SS, Kang DH. Alicyclobacillus spp. in the fruit juice industry: history, characteristics, and current isolation/detection procedures. Crit Rev Microbiol 2004;30:55–74. 35. Bui VN, Toussaint G, Laurenti D, et al. Co-processing of pyrolisis bio oils and gas oil for new generation of bio-fuels: hydrodeoxygenation of guaı¨acol and SRGO mixed feed. Catal Today 2009;143: 172–8. 36. Gutierrez A, Kaila RK, Honkela ML, et al. Hydrodeoxygenation of guaiacol on noble metal catalysts. Catal Today 2009;147:239–46. 37. Bykova MV, Ermakov DY, Kaichev VV, et al. Ni-based sol–gel catalysts as promising systems for crude bio-oil upgrading: guaiacol hydrodeoxygenation study. Appl Catal B 2012;113–114:296–307. 38. Nava B, Pawelec P, Castano MC, et al. Upgrading of bio-liquids on different mesoporous silica-supported CoMo catalysts. Appl Catal B 2009;92:154–67. 39. He W, Li Y, Si H, et al. Molecular modeling and spectroscopic studies on the binding of guaiacol to human serum albumin. J Photochem Photobiol A Chem 2006;182:158–67. 40. Bolton JL, Pisha E, Li S, et al. The reactivity of o-quinones which do not isomerize to quinone methods correlates with alkylcatecholinduced toxicity in human melanoma cells Chem Biol Interact 1997; 106:133–48. 41. Shirai K. Screening of microorganisms for catechol production from benzene Agric Biol Chem 1986;50:2875–80. 42. Dignum MJW, Kerler J, Verpoorte R. Vanilla production: technological, chemical, and biosynthetic aspects. Food Rev Int 2001;17: 119–20. 43. Held M, Schmid A, Kohler HPE, et al. An integrated process for the production of toxic catechols from toxic phenols based on a designer biocatalyst. Biotechnol Bioeng 1999;62:641–8. 44. Kauffman ME, Keener WK, Clingenpeel SR, et al. Use of 3-hydroxyphenylacetylene for activity-dependent, fluorescent labeling of bacteria that degrade toluene via 3-methylcatechol. J Microbiol Meth 2003;55:801–5. 45. Husken LE, Oomes M, Schroen K, et al. Membrane-facilitated bioproduction of 3-methylcatechol in an octanol/water two-phase system. J Biotechnol 2002;96:281–9. 46. Callizot N, Warter JM, Poindron P. Pyridoxine-induced neuropathy in rats: a sensory neuropathy that responds to 4-methylcatechol. Neurobiol Dis 2001;8:626–35.

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47. Liu C, Zhang Y, Huang X. Study of guaiacol pyrolysis mechanism based on density function theory. Fuel Proces Technol 2014;123: 159–65. ¨ ztu¨rk Sarikaya SB, Gu¨lc¸in I, _ Supuran CT. Carbonic anhydrase 48. O inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of phenolic acids. Chem Biol Drug Des 2010;75:515–20. ¨ ztu¨rk Sarikaya SB, Topal F, S 49. O ¸ entu¨rk M, et al. In vitro inhibition of a-carbonic anhydrase isozymes by some phenolic compounds. Bioorg Med Chem Lett 2011;21:4259–62. _ Scozzafava A, Supuran CT. Carbonic 50. Innocenti A, Gu¨lc¸in I, anhydrase inhibitors. Antioxidant polyphenol natural products effectively inhibit mammalian isoforms I–XV. Bioorg Med Chem Lett 2010;20:5050–3. 51. Innocenti A, Ozturk Sarikaya SB, Gulcin I, Supuran CT. Carbonic anhydrase inhibitors. Inhibition of mammalian isoforms I–XIV with a series of natural product polyphenols and phenolic acids. Bioorg Med Chem 2010;18:2159–64. _ Alici HA, Cesur M. Determination of in vitro antioxidant 52. Gu¨lc¸in I, and radical scavenging activities of propofol. Chem Pharm Bull 2005;53:281–5. _ Da¸stan A. Synthesis of dimeric phenol derivatives and 53. Gu¨lc¸in I, determination of in vitro antioxidant and radical scavenging activities. J Enzyme Inhib Med Chem 2007;22:685–95. _ Antioxidant activity of caffeic acid (3,4-dihydroxycin54. Gu¨lc¸in I. namic acid). Toxicology 2006;217:213–20. _ Antioxidant and antiradical activities of L-carnitine. Life 55. Gu¨lc¸in I. Sci 2006;78:803–11. _ Comparison of in vitro antioxidant and antiradical 56. Gu¨lc¸in I. activities of L-tyrosine and L-Dopa. Amino Acids 2007;32:431–8. _ Antioxidant activity of L-adrenaline: an activity–structure 57. Gu¨lc¸in I. insight. Chem Biol Interact 2009;179:71–80. _ Antioxidant properties of resveratrol: a structure–activity 58. Gu¨lc¸in I. insight. Innov Food Sci Emerg 2010;11:210–18. 59. Supuran CT. Diuretics: from classical carbonic anhydrase inhibitors to novel applications of the sulfonamides. Curr Pharm Des 2008;14: 641–8. 60. Ilkimen H, Yenikaya C, Sarı M, et al. Synthesis and characterization of a proton transfer salt between 2,6-pyridinedicarboxylic acid and 2-aminobenzothiazole, and its complexes and their inhibition studies on carbonic anhydrase isoenzymes. J Enzyme Inhib Med Chem 2014;29:353–61. 61. Scozzafava A, Mastrolorenzo A, Supuran CT. Carbonic anhydrase inhibitors and activators and their use in therapy. Expert Opin Ther Pat 2006;16:1627–64. 62. Innocenti A, Vullo D, Scozzafava A, Supuran CT. Carbonic anhydrase inhibitors: interactions of phenols with the 12 catalytically active mammalian isoforms (CA I–XIV). Bioorg Med Chem Lett 2008;18:1583–7. 63. Steele RM, Batugo MR, Benedini F, et al. Nitric oxide-donating carbonic anhydrase inhibitors for the treatment of open-angle glaucoma. Bioorg Med Chem Lett 2009;19:6565–70. 64. Alterio V, Hilvo M, Di Fiore A, et al. Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX. Proc Natl Acad Sci USA 2009;106:16233–8. 65. Ahlskog JKJ, Dumelin CE, Tru¨ssel S, et al. In vivo targeting of tumor-associated carbonic anhydrases using acetazolamide derivatives. Bioorg Med Chem Lett 2009;19:4851–6. 66. Dubois L, Lieuwes NG, Maresca A, et al. Imaging of CA IX with fluorescent labelled sulfonamides distinguishes hypoxic and (re)oxygenated cells in a xenograft tumour model. Radiother Oncol 2009;92:423–8. 67. Nair SK, Ludwig PA, Christianson DW. Two-site binding of phenol in the active side of human carbonic anhydrase II: Structural implications for substrate association. J Am Chem Soc 1994;116: 3659–60. 68. Maresca A, Temperini C, Vu H, et al. Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors. J Am Chem Soc 2009;131:3057–62. 69. Davis RA, Innocenti A, Poulsen SA, Supuran CT. Carbonic anhydrase inhibitors. Identification of selective inhibitors of the human mitochondrial isozymes VA and VB over the cytosolic isozymes I and II from a natural product-based phenolic library. Bioorg Med Chem 2010;18:14–18. 70. Senturk M, Gulcin I, Dastan A, et al. Carbonic anhydrase inhibitors. Inhibition of human erythrocyte isozymes I and II with a series of antioxidant phenols. Bioorg Med Chem 2009;17:3207–11.

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A. Scozzafava et al.

71. Akbaba Y, Akıncıog˘lu A, Go¨c¸er H, et al. Carbonic anhydrase inhibitory properties of novel sulfonamide derivatives of aminoindanes and aminotetralins. J Enzyme Inhib Med Chem 2014;29: 35–42. 72. Akincioglu A, Akbaba Y, Goc¸er H, et al. Novel sulfamides as potential carbonic anhydrase isoenzymes inhibitors. Bioorg Med Chem 2013;21:1379–85. _ 73. Nar M, C¸etinkaya Y, Gu¨lc¸in I, Menzek A. (3,4Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors. J Enzyme Inhib Med Chem 2013;28:402–6. 74. Barclay LRC, Vinqvist MR, Mukai K, et al. Chain-breaking phenolic antioxidants: steric and electronic effects in polyalkylchromanols, tocopherol analogs, hydroquinones, and superior antioxidants of the polyalkylbenzochromanol and naphthofuran class. J Org Chem 1993;58:7416–20. 75. Tomiyama S, Sakai S, Nishiyama T, Yamada F. Factors influencing the antioxidant activities of phenols by an ab initio study. Bull Chem Soc Jpn 1993;66:299–304. 76. Sethi KK, Verma SM, Tanc¸ M, et al. Carbonic anhydrase inhibitors: synthesis and inhibition of the cytosolic mammalian carbonic anhydrase isoforms I, II and VII with benzene sulfonamides incorporating 4,5,6,7-tetrachlorophthalimide moiety. Bioorg Med Chem 2013;21:5168–74. 77. Winum JY, Maresca A, Carta F, et al. Polypharmacology of sulfonamides: pazopanib, a multitargeted receptor tyrosine kinase inhibitor in clinical use, potently inhibits several mammalian carbonic anhydrases. Chem Commun 2012;48:8177–9. 78. Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin Ther Pat 2000;10:575–600. 79. Supuran CT. Carbonic anhydrase inhibitors and activators for novel therapeutic applications. Fut Med Chem 2011;3:1165–80. 80. Chohan ZH, Supuran CT, Scozzafava A. Metal binding and antibacterial activity of ciprofloxacin complexes. J Enzyme Inhib Med Chem 2005;20:303–7. 81. Supuran CT. Carbonic anhydrase inhibitors. Bioorg Med Chem Lett 2010;20:3467–74.

J Enzyme Inhib Med Chem, Early Online: 1–6

82. Supuran CT, Scozzafava A. Carbonic anhydrases as targets for medicinal chemistry. Bioorg Med Chem 2007;15:4336–50. 83. Ghorab MM, Alsaid MS, Ceruso M, et al. Carbonic anhydrase inhibitors: synthesis, molecular docking, cytotoxic and inhibition of the human carbonic anhydrase isoforms I, II, IX, XII with novel benzenesulfonamides incorporating pyrrole, pyrrolopyrimidine and fused pyrrolopyrimidine moieties. Bioorg Med Chem 2014;22: 3684–95. 84. Lou Y, McDonald PC, Oloumi A, et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 2011;71:3364–76. 85. Zo1nowska B, S1awinskia J, Pogorzelska A, et al. Carbonic anhydrase inhibitors. Synthesis, and molecular structure of novel series N-substituted N0 -(2-arylmethylthio-4-chloro-5-methylbenzenesulfonyl) guanidines and their inhibition of human cytosolic isozymes I and II and the transmembrane tumor-associated isozymes IX and XII. Eur J Med Chem 2014;71:135–47. 86. Rice-Evans CA, Miller NJ, Paganga G. Structure–antioxidant activity relationships of flavonoids and phenolic acids. Free Radical Biol Med 1996;20:933–56. 87. Sroka Z, Cisowski W. Hydrogen peroxide scavenging, antioxidant and anti-radical activity of some phenolic acids. Food Chem Toxicol 2003;41:753–8. 88. Go¨c¸er H, C¸etinkaya Y, Go¨ksu S, et al. Carbonic anhydrase and acetylcholine esterase inhibitory effects of carbamates and sulfamoylcarbamates. J Enzyme Inhib Med Chem. (in press) doi:10.3109/ 14756366.2014.928704. _ Alwasel S. Capsaicin: a potent inhibitor of 89. Arabaci B, Gu¨lc¸in I, carbonic anhydrase isoenzymes. Molecules 2014;19:10103–14. 90. Khalifah RG. The carbon dioxide hydration activity of carbonic anhydrase. I. Stop-flow kinetic studies on the native human isoenzymes B and C. J Biol Chem 1971;246:2561–73. _ Beydemir S 91. S ¸ entu¨rk M, Gu¨lc¸in I, ¸ , et al. In vitro inhibition of human carbonic anhydrase I and II isozymes with natural phenolic compounds. Chem Biol Drug Des 2011;77:494–9.

Carbonic anhydrase inhibitors: guaiacol and catechol derivatives effectively inhibit certain human carbonic anhydrase isoenzymes (hCA I, II, IX and XII).

Carbonic anhydrases (CAs) are widespread metalloenzymes in higher vertebrates including humans. A series of phenolic compounds, including guaiacol, 4-...
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