synthesis and pharmacological properties of … · 2014. 4. 20. · acyl chlorides the acid...

Synthesis and pharmacological properties of glutamic acid amides ФАРМАЦИЯ, том LIX, kн. 1-4/2012 85

Introduction

Amide is a derivative of carboxylic acids with a general formula of RCONH2, where R is hydrogen or an alkyl or an aryl radical. The amides are abundant in life, as proteins play a vital role in almost all biological processes. They present in many pharmaceutical sub-

stances. An in-depth analysis of the Comprehensive Medicinal Chemistry database reveals that the carbox-amide group appears in more than 25% of all known drugs [1]. Abbreviations used in the text are listed in Table 1. Examples of coupling reagents discussed in this review are added in Table 2.

SYNTHESIS AND PHARMACOLOGICAL PROPERTIES OF GLUTAMIC ACID AMIDES: A REVIEW

Y. Voynikov1, P. Peikov2, J. Tencheva1, Al. Zlatkov2, G.Stavrakov11Department of Chemistry,

2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Medical University – Sofia

Summary: The present study is a review of known methods and strategies for synthesis of amides with emphasis on glutamic acid (GA) amides. Amides can be prepared by activation of the corresponding car-boxylic acids to acyl halides (chlorides and fluorides), acyl azides, anhydrides or esters using various coupling reagents like carbodiimides (DCC, EDC, DIC, etc.), organophosphorous reagents (BOP, PyBOP, DPPA, etc.) or aminium reagents (HOBt, HBTU, TBTU, etc.). After activation subsequent reaction with the desired amine follows, to produce the amide. Discussed in this review are also the pharmacological proper-ties of GA amides as prodrugs. These prodrugs exhibit generally enhanced cell permeability, stability and bioavailability combined with good safety. Prodrugs with GA may be beneficial as a substantially improved oral administration form and warrant future research toward development of new drugs.

Key words: Amide synthesis, glutamic acid, glutamic acid amide, prodrug, coupling reagent

СИНТЕЗ И ФАРМАКОЛОГИЧНИ СВОЙСТВА НА АМИДИ НА ГЛУТАИМНОВАТА КИСЕЛИНА: ОБЗОР

Ю. Войников1, П. Пейков2, Ж. Тенчева1, А. Златков2, Г.Ставраков11Катедра Химия

2Катедра по Фармацевтична химия, Фармацевтичен факултет, МУ - София

Резюме: Настоящата статия е обзор на познати методи и подходи в синтеза на амиди и по-специално амиди на глутаминовата киселина. Амиди могат да се получат чрез активиране на съответните кар-боксилни групи до ацил халиди (хлориди и флуориди), ацил азиди, анхидриди или естери използ-вайки различни активиращи агенти като карбодиимиди (DCC, EDC, DIC, и др.), органофосфорни агенти (BOP, PyBOP, DPPA, и др.) или аминиеви агенти (HOBt, HBTU, TBTU, и др.). След активи-рането следва реакция с амина за да се получи желаният амид. Разглеждани са също фармаколо-гичните свойства на амидите с глутаминова киселина, като предлекарства. Те проявяват подобрена клетъчна проницаемост, стабилност, бионаличност и безопасност. Предлекарствата с глутаимнова киселина могат да намерят приложение като подобрени орални лекарствени форми, което е основа-ние за бъдещи изследвания към разработването на нови медикаменти.

Ключови думи: Амиден синтез, глутаминова киселина, амид на глутаминова киселина, предлекар-ство, активиращ агент

86 ФАРМАЦИЯ, том LIX, kн. 1-4/2012 Y. Voynikov, P. Peikov, J. Tencheva, Al. Zlatkov, G. Stavrakov

Table 1. Abbreviations


Table 2. Coupling Reagents


Synthesis of Amides

The reaction of a carboxylic acid with an amine, unlike the formation of an ester, is ineffi cient be-cause the amide bond formation has to overcome adverse thermodynamics and lies on the side of hy-drolysis rather than synthesis. Therefore, activation of the acid is necessary [1] (Scheme 1). Hence, a plethora of methods and strategies have been de-veloped. Different examples of these methods are present in this report. Carboxy components can be activated as acyl halides, acyl azides, anhydrides, esters etc [1].

Acyl Halides

The activation of carboxylic acids by conversion to the corresponding acyl halides is in principle the simplest approach to amide synthesis [2].

Acyl chlorides

The acid chloride method was fi rst introduced to peptide chemistry by E. Fisher in 1903. Since then, chlorination of amino acids was carried out with vari-ous chlorinating reagents such as pivaloyl chloride, phthaloyl dichloride, thionyl chloride, oxalic chlo-ride, etc [3].

Thionyl chloride (SOCl2), oxalyl chloride (COCl)2, phosphorus trichloride (PCl3), phosphorus oxychloride (POCl3) and phosphorus pentachloride

(PCl5) are commonly used to generate acyl chlorides from their corresponding acids [1]. The amide bond is formed by reaction of the acyl chloride with the desired amine (Scheme 2).

Acyl chlorides are prone to side reactions and racemization. Disadvantage is also the production of HCl, and the reagents to prepare acid halides are not compatible with complex or sensitive substrates. Simple acyl chlorides cyclize spontaneously to oxa-zolones [2].

Scheme 2. Aminolysis of acyl chloride

Acyl fl uorides

Acid fl uorides are stable, often crystalline and readily obtained by treating the acid with cyanuric fl uoride [2]. Compared to the chlorides, the acid fl uorides show greater stability towards water and a relative lack of conversion to the corresponding oxa-zolones upon treatment with organic bases and are more reactive towards amines [4]. The most notable advance in acid halogenation has been the introduc-tion of fl uoroamidinium salts by Carpino [5]. TFFH and BTFFH are stable, non-hygroscopic salts. They act in situ as fl uorinating reagents and are suitable both for solution syntheses and for solid-phase pep-

Scheme 1. Acid аctivation аnd Aminolysis


tide synthesis [4]. Acyl fl uorides react in the same way as acyl chlorides.

Acyl Azides

One of the advantages of the azide method is that azides can be formed directly from esters. The ester is converted to a hydrazide then transformed to an azide with either nitrous acid or an alkyl nitrite. An alterna-tive to hydrazinolysis of esters is the use of protect-ed hydrazides such as benzyloxycarbonylhydrazine whose protecting group can be removed later [2].

The most important side reaction in the azide ap-proach is the Curtius rearrangement, which occur especially at elevated temperatures that afford isocy-anates, which do not react with their precursors. The azide method is less prone to racemization than most other methods. Racemization does occur with excess base in polar solvents. Racemization may be avoided by carrying out the reaction at low temperature and high concentration of reactants, at the expense of

considerable time of reaction. This approach is still useful when racemization is a serious problem [1].

Anhydrides

Acid anhydrides give rapid acylation of most amines. However, only one of the two acyl groups is converted to an amide.

Carbodiimides

Carbodiimides are widely being used to promote the conversion of carboxylic acids to amides. In this method the carboxylic acid is treated with a carbodi-imides (Scheme 3). It was originally developed for creating the amide bonds in peptides by Sheehan and Hess in 1955. This mild and effi cient coupling meth-od is compatible with peptide formation. The main limitation is that only half of the acid is effectively coupled and the other half is wasted. This could be a problem if the acid is valuable [1].

Scheme 3. Anhydride preparation and coupling with amines


Anhydride preparation

Dicyclohexylcarbodiimide (DCC) has been pre-dominantly used and has been the single most impor-tant reagent for activating carboxyl groups in peptide synthesis for over fi fty years [4]. It has been used to activate symmetrical anhydrides, esters, or as a di-rect coupling agent. The formation of O-acylisourea is rapid and it subsequently reacts with the amine to form an amide bond and dicyclohexylurea, which precipitates immediately. Since most dialkylureas are sparingly soluble, their separations are relatively straightforward. The intermediates are highly reac-tive and side reactions may intervene, especially if the reaction with the amine is delayed. Collapse of the O-acylisourea by intra molecular acyl transfer competes with the attack by nucleophiles. The re-action between urea and the symmetrical anhydride forms an N-acylurea, which reduces the yield and makes purifi cation diffi cult [2].

This side reaction can be considerably diminished by reacting the acid and the coupling reagent at 0° before adding the amine. Furthermore, adding a se-lected nucleophile that reacts faster than the compet-ing acyl transfer and generates an intermediate still active enough to couple with the amine also prevents the side reactions. Such nucleophiles are DMAP and HOBt [1] (Scheme 4).

Since the successful launch of DCC/HOBt, car-

bodiimides have dramatically expanded their scope with the aid of various additives. These additives have complemented the weakness of coupling rea-gents by enhancing the reaction rate and reducing the racemisation [3].

Other well used carbodiimides are EDC and DIC. DIC is a moderately expensive liquid that is employed in solid-phase synthesis. It is especially helpful due to the enhanced solubility of its urea to avoid the obstacles presented by the use of DCC [4, 6]. EDC is an expensive crystalline material known as soluble carbodiimide because both the reagent and the corresponding ureas are soluble in water. EDC can be employed for amide-bond forming reactions in partially aqueous mixtures [6].

Active Esters

Active esters are often crystalline stable materials and are prepared by DCC-mediated coupling or by mixed anhydride methods. Active esters are at a low-er level of activation than some other intermediates previously described and they react selectively with the amine component. Active esters produce fewer side reactions during coupling, including racemiza-tion. However, when prepared directly racemization may occur if the carboxyl group is prone to epimeri-zation, especially in the presence of bases. They may be used in the temporary carboxyl blockade, which

Scheme 4. Use of HOBt to minimise the formation of unreactive N-acylurea


allows access to protected peptide active esters [2]. Activated esters such as aromatic esters are usually easier to hydrolyse than alkyl esters and are prone to react with a wide range of nucleophiles. More im-portantly, they cleanly react with amines under mild conditions with usually reduced racemisation [1].

Organophosphorous reagents

Carboxylic acids can also be activated by the for-mation of mixed anhydrides with various phosphoric acid derivatives. They were originally developed as an alternative to avoid the racemization and side re-actions that can occur with carbodiimides. Their use gives enhanced regioselectivity towards the carbonyl group of the phosphoric-carboxylic mixed anhydride [7, 8].

Benzotriazol-1-yl-oxytris-(dimethylamino)-phos-phonium hexafl uorophosphate (BOP), also called Castro’s reagent, is the fi rst published example of these HOBt-based uronium salt reagents. Advantage of BOP is that it does not generate asparagine and glutamine dehydration byproducts and racemization is minimal and is also useful for preparing esters un-der mild conditions. Coupling reactions are rapid, be-ing nearly complete within a few minutes. Although BOP must be handled with caution as highly carci-nogenic HMPA is formed as a byproduct in coupling reactions[1]. For this reason, the viable alternative PyBOP has been developed where the dimethylami-no groups are replaced by pyrrolidine substituents. PyBOP shows comparable performance to BOP, in some cases even better [4]. PyBOP couples amino acids as effi ciently as BOP, but the by-products are less hazardous. Coupling reactions are rapid, being nearly complete within a few minutes. PyBrOP is a more reactive coupling reagent. It is especially use-ful in diffi cult coupling, such as coupling N-meth-ylamino acids or α, α - dialkylglycines, where other

coupling reagents are ineffi cient [6]. DPPA is another effective reagent for conversion of amines to amides. The proposed mechanism involves formation of the acyl azide as a reactive intermediate [8]. DPPA can allow the coupling in high yield in the presence of a base in a single operation [2].

Another useful reagent for amide formation is a compound , known as BOP-Cl, which also proceeds by formation of a mixed carboxylic phosphoric an-hydride [8].

Li et al. [4] reported the new DEPBT with su-perior performance as coupling reagent. DEPBT is an effective coupling reagent for synthesis of linear and cyclic peptides by both solution and solid-phase peptide synthesis. DEPBT mediates amide bond for-mation with remarkable resistance to racemization. When DEPBT is used as a coupling reagent, it is not necessary to protect the hydroxy group of the amino component (such as tyrosine, serine, and threonine) and the imidazole group in the case of histidine [9].

In a recent paper McNulty et al. [10] reported a novel method for direct formation of esters and amides from carboxylic acids using only diethyl chlorophosphate 1 in pyridine under Yonemitsu con-ditions (Scheme 5). The reaction takes place selec-tively in the presence of an alcohol and sequentially in the presence of amines allowing access to useful ester, amide, and peptide analogs. All side products are water soluble allowing for the straightforward isolation of high purity products.

Although no diethylphosphate ester was pro-duced from the direct reaction of the alcohol with 1, the reaction of the same diethyl phosphate-activated carboxylic acid anhydrides with amines was not suc-cessful when done in the presence of the amine. Di-ethylphosphoramide side products were obtained, no doubt due to the higher nucleophilicity of the amine compared to the alcohol. However, simple sequential

Scheme 5. Direct amidation of acids and amines with diethyl chlorophosphate (1) in pyridine


addition of the amine to the activated acid complete-ly suppressed phosphoramide formation, resulting in high yields of the desired condensed amide products.

Advantage of diethyl chlorophosphate 1 include that it can be employed directly in the presence of the alcohol in pyridine. The nucleophilic carboxy-late anion attacks the activated derivative of 1 to form the mixed anhydride in preference to the alco-hol. Another advantage is that purifi cation is very straightforward since there are no hydrated organic side products (such as DEADH2, Ph3PO, and DCC-urea) to contend with as the phosphate and pyridin-ium salts formed are water soluble. Simply removing solvents and work-up from aqueous sodium bicarbo-nate/ethyl acetate yields the ester in relatively high purity (>95% in all cases so far investigated) without chromatographic purifi cation [10].

Aminium-based reagents

These reagents were believed to have a uronium structure, but crystal and solution structure studies revealed that these reagents actually have aminium structure [11]. Nevertheless, sometimes by custom, they are still called uronium type reagents.

The HOBt derived components HBTU and TBTU today belong to the most widely used reagents for peptide coupling and feature a broad application spec-trum. HBTU and TBTU differ only by their counter ions which has no signifi cant infl uence on the coupling rate or racemization [4]. Both are very effi cient peptide coupling reagents with little racemization (Scheme 6). Coupling reactions are complete in as little as six min-utes and when HOBt is added, racemization can be re-duced to insignifi cant levels [12].

Besides HBTU and TBTU, several other mem-bers of the uronium family are worthy of attention. The 7-aza-analogue of HBTU called HATU can be considered today’s gold standard of peptide coupling reagents [4]. HATU is the most reactive uranium reagent, however it can be cost prohibitive on large scales and is often used as last resort [7].

HATU is similar to HBTU, but reacts faster with less epimerization during coupling. HATU is pre-ferred to HBTU in most rapid coupling protocols and is utilized in the same manner as HBTU [6]. HBTU is more cost effective alternative and is acceptable for most coupling applications.

HCTU has been developed as an effective alterna-tive to HATU on industrial scales, the higher reactiv-ity of this species is attributed to the more reactive Cl-HOBt intermediate [7]. HCTU remains colorless through long synthesis sequences and presumably has greater stability. It is reported to be less aller-genic than other coupling reagents, but nonetheless it should be handled cautiously. DiFenza and Rovero have reported that HCTU showed reduced rates of racemization compared to BOP [6]. Glutamic Acid

The other names include – S-(+)-GA, L-GA, 2- aminoglutaric acid, and an anionic form known as glutamate. Studies over the last several years have explored the physiological role and therapeutic util-ity of these molecules in various disease conditions.

Prodrugs With Glutamic Acid

L-GA conjugated with paclitaxel is known to form a new anticancer agent called poly (LGA)- paclitaxel

Scheme 6. Coupling procedure using HBTU


(PG-TXL) with superior antitumor activity, favorable pharmacokinetic properties and/or mechanism of ac-tion different from that of paclitaxel alone. It is sug-gested that superior activity of PG-TXL may be due to continuous release of paclitaxel [13, 14].

In a double blind placebo-controlled study, ad-ministration of GA prevented the vincristine-induced neurotoxicity, a well known principal limiting side effect. The loss of tendo-Achilles refl ex as an objec-tive parameter of vincristine-induced neurotoxicity was reported to be signifi cantly higher in placebo group as compared to GA group. Intra thecal admin-istration of vincristine produced ascending paralysis and death, which was prevented by i.v. GA. Inhibi-tion of disruption of micro-tubular structures by GA have been proposed to play a role [15].

Kim et al. [16] synthesized and tested a novel quercetin-glutamic acid conjugate (Qu-GA) with increased water solubility, stability, and cell perme-ability compared with quercetin and QC12 (a water soluble glycine prodrug of quercetin). Quercetin has many physiological activities however the drug has pharmacokinetic problems such as low solubility in water and fast metabolism as well as excretion, which results in its low bioavailability.

A series of quercetin–amino acid conjugates were prepared through conversion of amino acids to the corresponding activated urethanes with Bis(4-nitro-phenyl) carbonate ((4-NO2-PhO)2CO), followed by alcoholysis with quercetin. Deprotection of the tert-butyl group by treatment with TFA provided the de-sired quercetin prodrugs.

In addition to quercetin–amino acid conjugates, two quercetin–dipeptide conjugates such as quer-cetin-alanine-aspartic acid (Qu-AD) and quercetin-alanine-glutamic acid (Qu-AE) were also prepared utilizing EDC/HOBt. The yield was 90% and 92% respectively.

It is believed that the human PepT1 might be at work in recognition as well as transport of quercetin prodrugs, resulting in increased absorption and ex-tended half-lifes compared with quercetin and QC12 [16].

Ninomiya et al. [17] synthesized several amino acid derivatives of tricin as prodrugs, to improve the oral bioavailability. The fl avone tricin has antioxi-dant activity, exhibiting antiviral, anti-infl ammatory,

antihistamic and anticancer effects. Several amino acids including GA were attached to the 4’-position of the tricin B ring. First, treatment of the amino acid tert-butyl esters with bis(4-nitrophenyl)carbonate was carried out, and then, tricin and the additional amine were added to the reaction mixture. The tert-butyl groups of the products were deprotected with TFA to yield the tricin-amino acid conjugates.

In addition, they synthesized tricin-dipeptide con-jugates T-Ala-Asp and T-Ala-Glu from T-Ala using the peptide-coupling reagent water-soluble carbodi-imide (WSC) and HOBt. Deprotections were carried out using TFA.

On the basis of a previous report that the querce-tin-dipeptide conjugate (Q-Ala-Glu as a regioisomer-ic mixture of the 3’-ester and 4’-ester of the quercetin B ring) had good cell permeability, Q-Ala-Glu was prepared and evaluated. Researchers have previously reported that modifi ed Ala-Asp- and Ala-Glu-benzyl esters as model prodrugs have an affi nity for peptide transporter PepT1 and effi cient permeabilities [18, 19]. Thus, this peptide transporter likely improves the oral absorption of T-Ala-Glu.

In all groups, plasma tricin concentrations after oral administration in male rats of T-Ala-Glu were substantially higher than after administration of in-tact tricin. These results suggest that T-Ala-Glu was actively absorbed through interaction with PepT1 and that inactivation by various metabolic enzymes was prevented.

In addition, T-Ala-Glu demonstrated a bimodal time course in the plasma profi le; the in vivo absorp-tion experiment revealed the existence of double site absorption which implies the possibility of rea-bsorption by enterohepatic circulation and intestinal absorption, because PepT1 is expressed in the GIT and kidney. Examination the oral toxicity effects of T-Ala-Glu in mice did not reveal any abnormal fi nd-ings. Among the prodrugs, the T-Ala-Glu exhibited enhanced permeability, stability in MDCK cells, and excellent bioavailability after oral administration in rats, with good safety [17].

Kumar et al. [20] synthesized several amide prodrugs of Diclofenac. The free carboxylic group of Diclofenac was temporarily masked by amino acid derivatives to prevent the direct exposure of the mucous layer of the stomach to this free car-


boxylic acid group. Diclofenac was made to react with derivatives of amino acids, via, several amino acid methyl esters including glutamic acid methyl ester in presence of HOBT, EDC. HCl and NMM, in dichloromethane. The yield of the glutamic acid ester derivative was 67%. High solubility in various organic solvents was observed for the newly syn-thesized prodrugs indicating the lipophilic behavior. All the synthesized prodrugs were found pharma-cologically active as compared to control and were quantitatively less active than standard Diclofenac. However, regarding the infl ammation inhibitory ac-tivity, the GA-Diclofenac derivative showed lower (30.65%) inhibitory activity compared to that of standard Diclofenac (66.66%).

Halie et al. [21] synthesized several peptidomi-metics of the tripeptide Arg-Gly-Asp (RGD). RGD is the motif of recognition of most integrins which are transmembrane receptors regulating cell attach-ment and response to the extracellular matrix. They are involved in many physiopathological processes like coagulation of blood, tumor-induced angiogen-esis, osteoporosis, etc. The peptidomimetics syn-thesized consisted of indolizin-3-one as a scaffold with two side chains bearing acidic (using different amino acids (including glutamic acid)) and basic (guanidine) function. To the indolizin-5-carboxylic acid dissolved in dichloromethane was added NMM and isobutyl chloroformiate to give the amide (88% yield). The following cleavage of the tert-butoxy groups was done by trifl uoroacetic acid TFA to give 72% yield of product. The compounds were evalu-ated in vitro for their ability to inhibit cell adhesion. Among the peptidomimetics tested, some showed inhibitory effect on S180 cell adhesion, but in gen-eral the results were not satisfactory and optimiza-tions are needed.

Zheng et al. [22] introduced different naturally oc-curring amino acids into anti-aggregation molecule 3S-tetrahydroisoquinoline-3-carboxylic acid (TIC). The main feature of this strategy was to design drug candidates in the form of dipeptide analogs that can be readily absorbed across the intestinal brush bor-der membrane via the peptide transport system. The analogs were with increased in vitro antiplatelet ag-gregation activities and in vivo antithrombotic activi-ties compared to TIC. Coupling of the amino acids

(including GA) was achieved using DCC/HOBt sys-tem and deprotection was carried out with aqueous sodium hydroxide.

Conclusion

Since the beginning of organic chemistry various methods to form an amide bond have been described. In the past two decades the design and synthesis of innovating coupling reagents has been an area of in-tense investigation.

The predominance of carbodiimide and active es-ter techniques has been gradually replaced with the so-called ‘onium salts’. Among these reagents, HOBt and HOAt based uronium, phosphonium and immo-nium salts are proving to be very effi cient. Anhy-drides, acylimidazoles and enzymes are still largely used and should be considered. However there is no method effective in every situation and the chemist should have to screen a variety of conditions to fi nd the method best adapted to his purpose.

Amino acid prodrug synthesis has been a strategy utilized to improve intestinal membrane permeability and increase aqueous solubility for different classes of drugs. The prodrugs reviewed in this article ex-hibit generally enhanced cell permeability, stability and bioavailability combined with good safety. It is believed that human PepT1 is involved in recognition as well as transport of many prodrugs, resulting in increased absorption and extended half-lives. Prod-rugs with GA may be benefi cial as a substantially im-proved oral administration form and warrant future research toward development of new drugs.

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coupling. - Tetrahedron, 61(46), 2005, 10827-10852.2. Joullié, M. and K. Lassen. Evolution of amide bond formation. -

Arkivoc, 8, 2010, 189-250.3. Han, S. Recent development of peptide coupling reagents in organic

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11. Abdelmoty, I. et al. Structural studies of reagents for peptide bond formation: Crystal and molecular structures of HBTU and HATU. - Lett. Pept. Sci., 1(2), 1994, 57-67.

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2009, 1164-1171.17. Ninomiya, M. et al. Increased Bioavailability of Tricin−Amino Acid

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18. Bailey, P.D. et al. How to Make Drugs Orally Active: A Substrate Template for Peptide Transporter PepT1. - Angewandte Chemie, 112(3), 2000, 515-518.

19. Nielsen, C.U. et al. Model prodrugs for the intestinal oligopeptide transporter: model drug release in aqueous solution and in various biological media. - J. Controlled Release, 73(1), 2001, 21-30.

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21. Halie, D. et al. Synthesis and evaluation of substituted indolizidines as peptidomimetics of RGD tripeptide sequence. - Tetrahedron, 65(7), 2009, 1402-1414.

22. Zheng, M. et al. (3S)-N-(l-Aminoacyl)-1,2,3,4-tetrahydroisoquino-lines, a class of novel antithrombotic agents: Synthesis, bioassay, 3D QSAR, and ADME analysis. - Bioorg. Med. Chem., 16(21), 2008, 9574-9587.

Address for correspondence: Yulian Voynikov Faculty of Pharmacy Department of Chemistry 2, Dunav str., 1000 Sofi a

рhone: +359 2 9236513 e-mail: [email protected]

Aдрес за кореспонденция: Юлиан Войников Фармацевтичен факултет Катедра Химия 1000 София, ул. Дунав 2

тел.:+359 2 9236513 e-mail: [email protected]

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