V. A. Davydova

Complex Compounds of Glycyrrhizic Acid with Antimicrobial Drugs

A promising direction in the development of new effective drugs is the synthesis of molecular complexes, for example, with cyclodextrins, which can protect parent substances from premature metabolic decay and provide for their transmembrane transport [1]. Previously, we suggested using 18 -glycyrrhizic acid (GA, I) as a complex-forming agent for the synthesis of new transport forms of the well-known drugs (nonsteroidal antiinflammatory agents, prostaglandins, uracils, etc.) and other biologically active substances [2 – 7]. In continuation of our work in the R&D of new GA-based preparations, we have synthesized a series of new molecular 1 : 1 complexes (II – XI) between antimicrobial drugs and GA (92 2 %) [8]

The synthesis and hepatoprotective activity of esters of the lupane group triterpenoids

Hemisuccinates, hemiphthalates, acetylsalicylates, cinnamates, andp-methoxycinnamates of lupeol, betulin, and 3-O-acetylbetulin were synthesized via interaction with corresponding acid anhydrides or acid chlorides. A number of betulin esters in position 3 and 28 were shown to exhibit a pronounced hepatoprotective effect similar to that of betulin and silibor. These experimental data were in a good agreement with the computer prediction of their biological activity. Betulin 3,28-bishemiphthalate was more effective than carsil in models of experimental hepatitis caused by carbon tetrachloride, tetracycline, and ethanol.

Synthesis and Antitumor Activity of Complex Compounds of β-Glycyrrhizic Acid with Antitumor Drugs

A promising way of creating new highly effective drugs is the synthesis of molecular complexes which can protect parent substances from premature metabolic decay and provide for their controlled release. A premise in our approach was that the complex-forming agent must contain both a hydrophilic component (binding the main parent substance) and a hydrophobic component (responsible for the drug transport). Previously, we demonstrated that the molecular complexes of -glycyrrhizic acid (I) with prostaglandins and nonsteroidal antiinflammatory drugs are characterized by reduced toxicity and increased therapeutic breadth as compared to those of the components [1 – 6]. The main disadvantage of the well-known antitumor drugs 5-fluorouracil (II), ftorafur (III), rubomycin (IV), and their analogs is high toxicity [7 – 9]. We have synthesized a series of complex compounds involving acid I and drugs II – V in 1 : 1 ratio. The molecular complexes of I with fluorouracil were obtained in a water – ethanol medium at ~50°C, and the complexes with anthracycline antibiotics, in ethanol at room temperature. All compounds were characterized by IR and UV spectra. The UV spectra of complexes I II and I III exhibit intense absorption maxima in the region of 250 – 260 nm, related to the total absorption of conjugated ketone and fluoropyrimidine chromophore groups. The UV spectra of complexes I IV and I V display intense maxima in the region characteristic of aromatic chromophores (234 – 235 nm) and new maxima related to anthracycline groups (470 – 530 nm). As can be seen from the data in Table 1, the complexes of I with compounds II – IV are less toxic than the initial antitumor drugs. According to the results of preliminary experiments, the molecular complex of acid I with drug III exhibits antitumor action with respect to Pliss lymphosarcoma, melanoma B-16, and Guerin’s carcinoma (Table 2).

Physicochemical Properties and Pharmacological Activity of Mn(II), Fe(II), Co(II), Cu(II), AND Zn(II) Gluconates

The well-known antitumor drugs suppress the immune system to different degrees [1]. It is therefore important to find substances possessing, in addition to antitumor activity, immunotropic properties. Of special interest in this respect are compounds of d-elements, an imbalance of which is known to accompany various pathological processes, including tumor growth [2 – 4]. The coordination compounds of these metals possess both immunomodulant properties [5 – 7] and cytotoxic activity [8 – 10]. It was reported that 3d-metal gluconates are effective correctors in some pathological states [11 – 14]. For this reason, we have synthesized gluconates of Mn, Fe, Co, Cu, and Zn (compounds I – V, respectively), determined some physicochemical properties of these compounds, and evaluated their cytotoxic and immunotropic activity. The compositions of gluconates I – V correspond to the general formula M(C6H11O7)2 2H2O, where M = Mn(II), Fe(II), Co(II), Cu(II), and Zn(II). The synthesized compounds were characterized by spectroscopic methods, thermogravimetric (TGA) and elemental analyses, and conductivity measurements in aqueous solutions. The IR absorption spectra of the synthesized compounds were analyzed in comparison to the spectra of the initial reagent, gluconic acid (VI), and the reference drug – calcium gluconate (VII). The IR spectra of metal gluconates display a strong absorption band at 1600 – 1588 cm – 1 and a medium-intensity band 1400 – 1420 cm – , corresponding to the antisymmetric and symmetric stretching vibrations of the carboxylate ion, respectively. In contrast, the spectrum of acid VI exhibits an absorption band at 1740 cm – , assigned to C=O of the COOH group. The formation of metal gluconates is always accompanied by almost complete vanishing of the absorption band at 1190 cm – 1 belonging to bending vibrations of the carboxy (C–O) group [15]. The absorption bands of bending vibrations of the secondary hydroxy groups OH, which are observed at 1220 – 1300 cm – 1 in the spectrum of calcium gluconate, shift to 1350 – 1400 cm – 1 in the spectra of compounds I – V. Significant differences between the IR spectra of gluconates and the spectra of gluconic acid and calcium gluconate are also observed for C–O of the secondary carboxy groups in the region of 1080 – 1135 cm – 1 and for their skeletal vibrations at 1000 – 1080 cm – 1 (Fig. 1). These distinctions indicate that these groups are involved in the formation of donor – acceptor groups with d-metal ions. Larsson [16] explained the observed character of absorption in this region by the formation of a chelate ring upon the complexation of d-elements with oxy acids. The results of C NMR measurements showed (Table 1) that this binding is mediated by the oxygen atom of a hydroxy group at the third carbon atom. This conclusion is confirmed by stereochemical considerations. Calculations by the AMPAK program using the AM-1 method, as well as the published data [17], indicate that the structure of molecule VI contains a fragment convenient for the formation of a six-member chelate cycle involving oxygen atoms of the carboxy group and the hydroxy group at the third carbon atom.

Synthesis of Glycyrrhizic Acid from Glycyrram and Pharmaciological Characterization of the Product

Glycyrrhizic acid (I) is an active component of licorice root extract obtained from plants of the Glycyrrhiza glabra L. and Glycyrrhiza uralensis Fisher species. The derivatives of acid I possess a broad spectrum of pharmacological properties, including antiinflammatory, antiulcer, antiallergic, antidote, antiviral, and some other types of activity [1]. Glycyrrhizic acid and its salts were recommended for the treatment of various forms of skin and liver cancer [2, 3] and are successfully used in the form of Stronger Neo-Minophagen C (SNMC) preparation for the therapy of patients with AIDS and hepatitis B [4, 5]. A purified glycoside component enters into the drug Clatraprostin (a veterinary preparation) and is used in the new medicinal forms of nonsteroidal antiinflammatory drugs and some other preparations [6, 7]. Previously [8] we proposed a method of obtaining purified glycyrrhizic acid (84 – 89%) from a commercial dry licorice root extract containing 26 – 28% of glycosides (available from the Urals Licorice Plant). Another commercial raw material that can be used for the synthesis of glycyrrhizic acid is glycyrram – a monoammonium salt of glycyrrhizic acid (available from the Chimkentbiofarm corporation). Glycyrram is an antiinflammatory drug used for the treatment of bronchial asthma, eczemas, and allergic dermatitis [9]. For the synthesis of pure glycyrrhizic acid from a commercial monoammonium salt, Volan and Dumazert [10] recrystallized the commercial product from acetic acid (AcOH) and ethanol, after which the purified glycoside was converted into a tripotassium salt (3K-salt) (II). Finally, salt II was converted into glycyrrhizic acid by acidification with an aqueous H 2 SO 4 solution. I: R = R = H, II: R = R = K, III: R = K, R = H.

Synthesis and Antiinflammatory Activity of 3-Thiabis(cyclohexanecarboxylic) Acid Derivatives

The class of antiinflammatory drugs includes a group of sulfur-containing organic compounds such as metiazinic acid, tinoridine (kenfamin), tiaramide (solantol), etc. However, all these drugs give rise to side effects, including gastrointestinal tract disorders. A pronounced antiinflammatory activity was reported for patented cyclic hydroxysulfones [1], the most active of which was 3-hydroxytetrahydrothiophene-1,1-dioxide (3-hydroxysulfolan). The results of investigations carried out in the Laboratory of New Drugs at the Institute of Organic Chemistry (Ufa) showed that most of the synthetic sulfones possess a more or less pronounced antiinflammatory activity. The maximum activity was observed for dihydroxysulfolan, producing, in contrast to most of the known antiinflammatory sulfur-containing compounds, no ulcerogenic action. The purpose of this work was to synthesize and characterize a series of new 3-thiabis(cyclohexanecarboxylic) acid derivatives. The condensation of piperylene (Ia) with acrylic acid nitrile (II) was conducted by the method described in [2 – 4] to obtain 2-methyl-1,2,5,6-tetrahydrobenzonitrile (IIIa) with a yield of 90%. As was previously established by A. A. Petrov and A. F. Sapozhnikova for an initial mixture containing cis and trans forms of piperylene in a 50 : 50 ratio, the condensation with acrylonitrile at 130 – 135°C involves only the trans form, whereas the cis form does not enter the reaction at this temperature. However, a complete condensation takes place at 180°C, when the cis to trans conversion obviously takes place. We conducted the condensation process with a cis– trans mixture for 12 h at 140°C; the unreacted cis-piperylene was distilled off. The synthesis was conducted according to the following scheme. I – V: R = Me (a), H (b); VI: R = Me (a – c), H (d); R = C4H8NO (a, b, d), C5H10N (c); X = H (a), Na (b – d).

Synthesis and hepatoprotector activity of 2-arylidene methylbetulonate derivatives

Betulinic acid (I), representing triterpenoids o f the lupane group, was isolated as long ago as in the beginning of the 20th century [ 1 ]. However, it was not until recent years that this compound drew the attention of pharmacists by showing a broad spectrum of biological activity, including antitumor and antiviral properties [2 8]. Below we report on the synthesis of new 2-arylidene derivatives of betulonic acid methyl ether (Ilia IIIg) obtained by transformation of the triterpenoid A ring. We have also studied the hepatoprotector activity of compounds Illb and llIg. Previously we have demonstrated this type of activity in some betulin esters [9]. Compounds Ilia IIIg were synthesized using the interaction of methylbetulonate (II) with aromatic aldehydes in alcoholic alkali solutions, the products being obtained at a 81 9 0 % yield. The proposed structures of the synthesized compounds were confirmed by data of 1R, UV, and NMR spectroscopies (Tables 1 and 2) and by agreement with the data published for betulonic acid [6, 10, 11], The IR spectra of compounds I l i a IIIg contained, besides the absorption bands characteristic of betulonic acid, the bands at 1610 1600 cm I belonging to vibrations in the aromatic rings. The 13C NMR spectra exhibit additional signals due to carbon atoms of the aromatic substituents (in the region of ~ = 110.5 159.3 ppm), while the signal of C-2 carbon of the aglycon shifts toward weaker fields (from 8 = 33.6ppm for betulonic acid to 131.9137.1 for compounds Ilia IIIg). In the IH NMR spectrum, the proton sig-

Isolation and biological activity of lipids from licorice (Glycyrrhiza glabra) roots

Hexane extract of licorice (Glycyrrhiza glabra L.) roots was obtained and investigated. Hydrocarbons, sterol ethers, triacylglycerides, free fatty acids, and free sterols were identified. The extract contains 70% neutral and 30% polar lipids. It is established that the lipid fraction of licorice roots is more effective than the analogous fraction of rosehip oil in stimulating the reparative regeneration of skin. In addition, this fraction also exhibits pronounced antiinflammatory and antiulcer effects, while being virtually nontoxic. Based on these results, the lipid fraction of licorice roots can be recommended as a parent substance for creating effective preparations in various medicinal forms.

Synthesis and Local Anesthetic Activity of ortho-(Cyclopentenyl)- and ortho-(Cyclopentyl)-aniline Derivatives

Recently [1, 2], we reported on the synthesis of compounds possessing local anesthetic and analgesic properties in the series of -aminoacetyl derivatives of 2-pentenyland 2-cyclopentenylanilines. In continuation of the research in this direction, we have synthesized and characterized a series of -aminoacetanilide hydrochlorides obtained from ortho-(cyclopent-1and -2-enyl)anilines and cyclopentylanilines and N-piperidinylacetocyclopent[b]indoline hydrochloride. In the first step, we obtained 2-methyl(I), 2,4-dimethyl-6-(cyclopenten-2 -yl)(II), and 2,2-di(cyclopenten-2 l)anilines (III) using the well-known method The subsequent reduction of double bonds in the alkenyl fragment of arylamines I – III readily proceeds on skeletal nickel catalyst Nisk) in ethyl alcohol with a quantitative yield of ortho-(cyclopentyl)anilines IV – VI. The only disadvantage of this method is the impossibility of regenerating used nickel catalyst subject to rapid poisoning. Heating compound I with KOH at 300°C leads to a vinyl shift of the double bond toward the aromatic nucleus (as described in [5]), which results in the formation of 2-methyl-6-(cyclopent-1 enyl)aniline (VII) with an almost quantitative yield. Indoline VIII was synthesized from aniline and 3-chlorocyclopentene as described in [6] By chloroacetylating arylamines I – VIII, we obtained 2-methyl-6(IX), 2,4-dimethyl(cyclopenten-2 -yl)(X), 2-methyl-6-(cyclopenten-1 -yl)(XI), 2-methyl-6(XII), 2,4-dimethyl-6-(cyclopentyl)(XIII), and 2,6-di(cyclopentyl)(XIV) -N-chloroacetanilides, as well as N-chloroacetyl-1,2,3,3a,4,8b-hexahydrocyclopent[b]indole (XV). The condensation of chloroacetanilides IX – XIV and indoline XV with piperidine in toluene leads to the formation of N-[2 -methyl-6 (XVI), N-[2 -dimethyl-6 -(cyclopen ten-2 -yl)](XVII), N-[2 -methyl-6 -(cyclopent-1 -enyl)phenyl](XVIII), N-[2 -methyl-6 (XIX), N-[2 -dimethyl-6 -(cyclopentyl)-phenyl](XX), N-[2 ,6 -di(cyclopentyl)phenyl](XXI) -amino-2-oxoethylpiperidines and N-(1,2,3,3a,4,8b-hexahydrocyclopent[b]indolyl)-2-oxoethylpiperidine (XXII). Bubbling gaseous HCl through hexane solutions of amines XIV – XXII leads to precipitation of hydrochlorides XXIII – XXIX, the aqueous solutions of which were tested for local anesthetic activity.

Synthesis and wound-healing and antiulcer activity of a chitosan-rhodium(III) complex

The experiments were performed with chitosan prepared from FarEast crab shells (P = 1100; deacetylation degree, 75%; particle size, 0 .250-0 .315mm). A polysaccharide metal complex was synthesized at room temperature in an aqueous medium (pH 7). To a weighed amount of the ligand was added with stirring an aqueous RhC13 solution so as to provide for a 6 : 1 molar ratio of the elemental chitosan chain units to metal. After a 2-h reaction, the adduct (complex) was washed with water and acetone and dried in vacumn. The IR absorption spectra were measured on a Specord M-80 spectrophotomeer (Germany) using samples pelletized with KBr. The content of rhodium in the complex was determined by elemental analyses (Table l) and by analysis of the products of complex decomposition with tin chloride [ 15].