Yasin Çetinkaya

Synthesis and carbonic anhydrase isoenzymes I, II, IX, and XII inhibitory effects of dimethoxybromophenol derivatives incorporating cyclopropane moieties.

Cyclopropylcarboxylic acids and esters and cyclopropylmethanols incorporating bromophenol moieties were investigated as inhibitors of the carbonic anhydrase enzyme (CA; EC 4.2.1.1). The cis- and trans-esters 5 and 6 were obtained from the reaction of 4-allyl-1,2-dimethoxybenzene (4) with ethyl diazoacetate, which after bromination with Br2 gave two isomeric monobromides (11 and 15), four isomeric dibromides (12, 13, 16, and 17), and two isomeric tribromides (14 and 18). The carboxylic acids 7, 8, and 19-26 were thereafter obtained by hydrolysis of the synthesized esters. All these bromophenol derivatives were tested against human (h) CA isoenzymes I and II (cytosolic, ubiquitous isoforms) and hCA IX and XII (transmembrane, tumor-associated enzymes). All tested bromophenols exhibited excellent inhibitory effects, in the low nanomolar range, with Ki values in the range of 0.54-59 nM against hCA I and in the range of 0.97-12.14 nM against hCA II, whereas they were low micromolar inhibitors against hCA IX and XII. The best hCA I inhibition was observed in new bromophenol derivative 20 (Ki = 0.54 nM). On the other hand, new bromophenol derivative 12 showed a powerful inhibition effect against hCA II (Ki = 0.97 nM).

Antioxidant and acetylcholinesterase inhibition properties of novel bromophenol derivatives.

In this study, series of novel bromophenol derivatives were synthesized and investigated for their antioxidant and AChE inhibition properties. Novel brominated diarylmethanones were obtained from the acylation reactions of benzoic acids with substituted benzenes. One of the bromodiarylmethanone was synthesized from the bromination of diarylmethanone with molecular bromine. All diarylmethanones were converted into their bromophenol derivatives with BBr3. The antioxidant activities of all synthesized compounds were elucidated by using various bioanalytical assays. Radical scavenging activities of compounds 10-24 were evaluated by means of DPPH and ABTS(+) scavenging activities. In addition, reducing ability of 10-24 were determined by Fe(3+), Cu(2+), and [Fe(3+)-(TPTZ)2](3) reducing activities. α-Tocopherol, trolox, BHA, and BHT were used as positive antioxidant and radical scavenger molecules. On the other hand, IC50 values were calculated for DPPH, ABTS(+) scavenging, and AChE inhibition effects of novel compounds. The results obtained from the current studies clearly show that novel bromophenol derivatives 20-24 have considerable antioxidant, antiradical, and AChE inhibition effects.

(3,4-Dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and its derivatives as carbonic anhydrase isoenzymes inhibitors

In this study, we have synthesised (3,4-dihydroxyphenyl)(2,3,4-trihydroxyphenyl)methanone and a series of its derivatives (5, 13–16) and tested the ability of these compounds to inhibit two metalloenzyme human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes, hCA I and hCA II. The synthesised compounds showed inhibitory effect on hCA I and hCA II isozymes. The results showed that synthesised compounds (5, 13–16) demonstrated the best inhibition activity against hCA I (IC50: 3.22–54.28 μM) and hCA II (IC50: 18.52–142.01 μM). The compound 14 showed the highest inhibiton effect against hCA I (IC50: 3.22 μM; Ki: 1.19 ± 1.4 μM). On the other hand, the compound 13 showed the highest inhibiton effect against hCA II (IC50: 18.52 μM; Ki: 3.25 ± 1.13 μM).

Synthesis and carbonic anhydrase isoenzymes inhibitory effects of brominated diphenylmethanone and its derivatives.

Known and novel derivatives including CO, Br, and OH (benzylic and phenolic), and the corresponding benzylic alcohols of (3,4‐dimethoxyphenyl)(2,3,4‐dimethoxyphenyl)methanone were synthesized, and their inhibitory effects on the carbonic anhydrase (CA) isoenzymes I and II were investigated. CAs are the metalloenzymes catalyzing the reversible hydration of carbon dioxide (CO2) to bicarbonate (HCO3−). The inhibitory effects of diphenylmethanone derivatives 5–18 were tested on human CA (hCA, EC 4.2.1.1) isoenzymes (hCA I and hCA II) and they inhibited both isoenzymes at micromolar levels. Compounds 5 and 10 were found to be the best inhibitors against both CA isoenzymes. According to our data, compound 10 was the best inhibitor for isoenzyme hCA I (IC50 = 3.48 µM, Ki = 2.19 µM) whereas compound 5 was found to be the best inhibitor for isoenzyme hCA II (IC50 = 1.33 µM, Ki = 2.09 µM). Probably, stable conformations of 5 and 10 are more convenient for interaction with CA isoenzymes than those of the other compounds.

Synthesis and Antioxidant Properties of (3,4‐Dihydroxyphenyl)(2,3,4‐trihydroxyphenyl)methanone and Its Derivatives

(3,4‐Dihydroxyphenyl)(2,3,4‐trihydroxyphenyl)methanone (5) and its two derivatives with bromine were synthesized from reactions such as bromination and demethylation of (3,4‐dimethoxyphenyl)(2,3,4‐trimethoxyphenyl)methanone (6). The Wolf‐Kishner reduction product (9) of 6 and its three derivatives with bromine were obtained. 4‐(3,4‐Dihydroxybenzyl)benzene‐1,2,3‐triol and its dibromide derivative (16) were also synthesized from 9 and the corresponding dibromide derivative. The in vitro antioxidant activities of nine new compounds synthesized in these reactions were determined by analyzing the radical scavenging activities of bromophenols for 2,2′‐azino‐bis(3‐ethylbenzthiazoline‐6‐sulfonic acid) (ABTS), 1,1‐diphenyl‐2‐picryl‐hydrazyl (DPPH), N,N‐dimethyl‐p‐phenylenediamine (DMPD), and the superoxide anion radical (

Synthesis and carbonic anhydrase isoenzymes I and II inhibitory effects of novel benzylamine derivatives.

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The effects of some bromophenols on human carbonic anhydrase isoenzymes.

) and examining the total reducing power through Fe3+‐Fe2+ transformation, FRAP and CUPRAC assays and the ferrous ions (Fe2+) chelating activities. Moreover, the results of these activities were compared to those of standard antioxidant compounds such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), α‐tocopherol, and trolox. The results showed that the synthesized bromophenols had effective antioxidant power. The phenol 5 with two phenolic rings and five phenolic hydroxyl groups was the most potent antioxidant and radical scavenger. In conclusion, the new compounds are promising molecules to be used owing to their potential antioxidant properties.

Synthesis of 4‐[2‐(3,4‐dimethoxybenzyl)cyclopentyl]‐1,2‐dimethoxybenzene derivatives and evaluations of their carbonic anhydrase isoenzymes inhibitory effects

Abstract Synthesis and carbonic anhydrase inhibitory properties of novel diarylmethylamines 22–25 and sulfonamide derivatives 26–28 were investigated. Acylation of methoxy-substituted benzenes with benzene carboxylic acids, reduction of ketones with NaBH4, conversion of alcohols to azides, Pd-C catalyzed hydrogenation of azides afforded title compounds 22–25. Compounds 22, 24 and 25 were converted to sulfonamide derivatives 26–28 with MeSO2Cl. The inhibitory effects of novel benzylamine derivatives 22–28 were tested on human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes hCA I and II. The results demonstrated that compound 28 was found to be the best inhibitor against both hCA I (Ki: 3.68 µM) and hCA II (Ki: 9.23 µM).

Photooxygenation of 5- and 6-chloro-1,3-cycloheptadienes and reactions of their endoperoxides with base: effects of the chloro substituent on the reactions

Abstract 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 () 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.

(1RS,2RS,3SR,5RS,7RS)-2,5-Dichloro-8-oxabicyclo­[5.1.0]octan-3-ol

Rearrangement of 1,6‐bis(3,4‐dimethoxyphenyl)hexane‐1,6‐dione (8) gave two isomeric products having cyclopentene moiety. Starting from the major product (3,4‐dimethoxyphenyl)[2‐(3,4‐dimethoxyphenyl)cyclopent‐1‐en‐1‐yl]methanone (11), eight new compounds (16–23) were obtained by the reactions such as reduction (by catalytic hydrogenation and NaBH4), nitration, 1,4‐addition, bromination, and esterification reactions. Carbonic anhydrases (CA, E.C.4.2.1.1) are ubiquitous metalloenzymes present in almost all living organism that catalyze a simple reaction, the conversion of carbon dioxide (CO2) and water (H2O) to bicarbonate ion (HCO3−) and a proton (H+). CA isoenzymes I and II (hCA I and II) inhibition effects of synthesized eleven new and four known compounds (8–13 and 15–23) were investigated. Inhibition studies of the hCA I and II with 4‐[2‐(3,4‐dimethoxybenzyl)cyclopentyl]‐1,2‐dimethoxybenzene derivatives revealed that they possess effective inhibitory potency. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized 4‐[2‐(3,4‐dimethoxybenzyl)cyclopentyl]‐1,2‐dimethoxybenzene derivatives with Kis in the range of 313.16–1537.00 nm against hCA I and in the range of 228.31–1927.31 nm against hCA II, respectively.