Pharmaceutical Chemistry Journal (v.49, #12)

Pharmacokinetic Study of Oxidized Dextrans by A. A. Starostenko; A. V. Troitskii; V. S. Medvedev; E. P. Gulyaeva; T. N. Bystrova; V. A. Shkurupii (795-797).
Methods of obtaining biotinylated oxidized dextran (BTOD) and procedures for pharmacokinetic studies of BTOD and biotinylated dextran (BTD) are described. The pharmacokinetics results showed that there are no differences in principle between the oxidized and unoxidized dextrans. All studied dextrans were characterized by two-phase pharmacokinetic profiles after intraperitoneal and subcutaneous administration.
Keywords: oxidized dextran; pharmacokinetics; biotin; immunoenzymatic assay

Design, Synthesis and Biological Evaluation of 2-Phenoxy-N-Phenylacetamides as Novel Anticancer Agents by Yuanyuan Shan; Fengzhi Liu; Ying Ma; Te Fan; Maoyi Wang; Yalin Dong (798-803).
A series of 2-phenoxy-N-phenylacetamides were designed and synthesized with a view to develop novel anticancer agents. All compounds were prepared with varied substitutions in the phenyl ring of aniline and evaluated for their anticancer activity. The majority of them displayed a moderate degree of cytotoxicity against several human cancer cell lines. Six compounds displayed potent cell growth inhibitory activity with IC50 values below 20 μM. Two compounds (TC-5 and TC-14) exhibited the most pronounced antiproliferative activity equivalent to or higher than that of positive control. The structure – activity relationship of these anticancer agents has been reviewed. The results indicate that incorporation of halogen into the benzene ring is beneficial for anticancer activity.
Keywords: 2-phenoxy-N-phenylacetamides; anticancer agents; tyrosine kinase; KDR; EGFR

Synthesis, Hydrolytic Stability, and Antileukemic Activity of Azacytidine Nucleoside Analogs by T. S. Bozhok; E. N. Kalinichenko; B. B. Kuz’mitskii; M. B. Golubeva (804-809).
New azacytidine nucleoside analogs with modified carbohydrate moieties were synthesized. Screening identified a highly active 2′-fluoro-containing azacytidine analog that could potentially be of interest as an agent for treating acute myelogenous leukemia and myelodysplastic syndrome.
Keywords: myelodysplastic syndrome; azacytidine; glycosylation; fluoro-deoxynucleosides; hydrolytic stability; antileukemic activity

Synthesis and Antimycobacterial Activity of 5-(Arylmethylene)Hexahydropyrimidine-2,4,6-Triones by S. A. Luzhnova; A. G. Tyrkov; N. M. Gabitova; E. A. Yurtaeva (810-812).
A series of 5-(arylmethylene)hexahydropyrimidine-2,4,6-triones were synthesized. Their antimycobacterial activity and acute daily toxicity with respect to M. lufu were investigated.
Keywords: synthesis; 5-(arylmethylene)hexahydropyrimidine-2,4,6-triones; antimycobacterial activity; minimum inhibiting and bactericidal concentrations; acute toxicity

Cryosynthesis and Properties of Dehydroepiandrosterone Hormone Nanoparticles by Yu. N. Morozov; D. V. Chistyakov; A. Yu. Utekhina; A. A. Astakhova; N. P. Goncharov; M. G. Sergeeva; G. B. Sergeev (813-816).
Nanoparticles of the steroidal hormone dihydroepiandrosterone (DHEA) were prepared by cryosynthesis technology, which allowed starting DHEA particles of size (100 ± 50) μm to be converted to nanoparticles of size (100 ± 20) nm. The particle sizes were determined by optical, electron transmission, and scanning atomic-force microscopy. HPLC with mass-spectrometric detection of starting and modified DHEA samples showed that the hormone molecular structure did not change during cryosynthesis of the nanoparticles. A comparison of the cytotoxicities of the samples on C6 glial cell culture showed that modified DHEA was less toxic. The results indicated that cryosynthesis technology could be used effectively to prepare nanoparticles of steroidal hormones.
Keywords: dihydroepiandrosterone; nanotechnology; cryosynthesis; C6 cell line; steroidal hormones; cytotoxicity

Synthesis and Cytotoxic Activity of Ethyl 2-Amino-1-Benzamido-4-Oxo-5-(2-Oxo-2-Arylethylidene)- 4,5-Dihydro-1H-Pyrrole-3-Carboxylates by S. S. Zykova; A. R. Galembikova; B. R. Ramazanov; T. F. Odegova; N. M. Igidov; M. A. Kiselev; S. V. Boichuk (817-820).
Recyclization of 5-aryl-2,3-dihydro-2-furandione 3-benzoylhydrazones (I) induced by cyanoacetic ester produced ethyl 2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylates (IIa-g). The biological activity of the synthesized compounds, which possessed low toxicities, was investigated. Ethyl 2-amino-1-benzamido-5-[2-(4-chlorophenyl)-2-oxoethylidene]-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylate (IIf) and the 5-[2-(3,4-dimethoxyphenyl)-2-oxoethylidene] analog (IIc) exhibited the greatest cytotoxicities against several connective-tissue tumor cell lines, namely, gastrointestinal stromal tumors (GISTs), osteosarcoma U2OS, and leiomyosarcoma SK-LMS-1. Ethyl 2-amino-1-benzamido-4-oxo-5-[2-oxo-2-(p-tolyl)ethylidene]-4,5-dihydro-1H-pyrrole-3-carboxylate (IIa) suppressed significantly tumor growth of GIST, LMS, and OS cell lines. Its activity against GIST cells at 10 μM was comparable with that of imatinib (1 μM) and, at lower concentrations (2.5 and 5 μM), with those of doxorubicin (0.25 μg/mL) and etoposide (40 μM), and exceeded significantly those of taxol (1 μM) and hydroxyurea (1 mM). The cytotoxicities of most of the studied compounds at 10 μM against SK-LMS-1 and U2OS cells in vitro were significantly greater than all reference drugs (doxorubicin, taxol, etoposide, etc.).
Keywords: ethyl 2-amino-1-benzamido-4-oxo-5-(2-oxo-2-arylethylidene)-4,5-dihydro-1H-pyrrole-3-carboxylates; acute toxicity; cytotoxicity; gastrointestinal stromal tumors (GISTs); leiomyosarcoma; osteosarcoma; chemotherapy; drug resistance

Synthesis and Antibacterial Activity of Bis-[1-(Adamantan-1-Yl)Ethyl]Amine Hydrochloride by V. I. Krylov; S. V. Moiseev; A. A. Kutin; N. G. Sakhno; O. V. Gunar; V. A. Yashkir; V. A. Merkulov (821-824).
An impurity in rimantadine hydrochloride drug substance that was previously undescribed in regulatory documents and the literature was identified. Its structure was elucidated and confirmed by a convergent synthesis. A method for synthesizing bis-[1-(adamantan-1-yl)ethyl]amine hydrochloride under laboratory conditions was developed. The antibacterial activity of the synthesized compound was assessed.
Keywords: rimantadine hydrochloride; bis-[1-(adamantan-1-yl)ethyl]amine hydrochloride; synthesis; antibacterial activity

A series of novel mono- and disubstituted p-tert-butylcalix[4]arene derivatives functionalized with gamma-aminobutyric acid (GABA) and its methyl ester were synthesized and screened in vivo for anticonvulsant activity by determining the minimum effective doses of pentylenetetrazole inducing clonic-tonic convulsions and tonic extension. Calixarene derivative X with one acetic acid and one GABA ester on the lower rim of the macrocyclic scaffold was characterized as possessing prolonged anticonvulsant activity. A relationship between the pharmacological effect and the number of amino-acid residues was found. Disubstituted calixarenes IV and IX demonstrated higher anticonvulsant activity 24 h after administration than the monosubstituted analogs.
Keywords: calix[4]arene; gamma-aminobutyric acid; anticonvulsant activity

Synthesis and Neurotropic Activity of New Pyrano[3,4-b]Furo[2,3-b]Pyridine Derivatives by V. V. Dabaeva; M. R. Bagdasaryan; A. S. Noravyan; Zh. V. Kazaryan; I. A. Dzhagatspanyan; I. M. Nazaryan; A. G. Akopyan (830-833).
New methods for synthesizing pyrano[3,4-b ]furo[2,3-b]pyridine derivatives from 7,7-dimethyl-2-oxo-3-cyano-1,2,7,8-tetrahydro-5H-pyrano[4,3-b ]pyridine were developed. Their neurotropic activity was investigated.
Keywords: synthesis; pyrano[3,4-b ]furo[2,3-b ]pyridine; neurotropic activity

Effect of Total Flavonoids from Vexibia alopecuroides on the Course of Experimental Diabetes in Rats by N. Kh. Yuldasheva; F. R. Égamova; G. I. Ismailova; Z. A. Khushbaktova; S. M. Yusupova; V. N. Syrov (834-837).
Total flavonoids from Vexibia alopecuroides administered for two weeks to rats with alloxan diabetes lowered the blood glucose level and increased the lactic-pyruvic acid redox potential and liver glycogen level. Lipid metabolism, the antioxidant protection system, and peroxidation processes showed a distinct tendency to normalize in vivo through the influence of the total flavonoids. In this respect, total flavonoids from V. alopecuroides were as effective in the conducted experiments as the known anti-diabetes agent diabeton.
Keywords: total flavonoids from Vexibia alopecuroides ; diabeton; alloxan diabetes; carbohydrate—lipid metabolism; antioxidant protection; lipid peroxidation

Method Development for Quantitative Determination of Ormustine in Biological Fluids by High Performance Liquid Chromatography with Mass-Spectrometric Detection by N. A. Pyataev; P. S. Petrov; A. A. Burtasov; O. V. Minaeva; O. A. Kulikov; K. G. Gurevich; A. V. Zaborovskii; V. P. Krasnov; A. V. Kokorev; G. S. Stolyarov; N. N. Zyrnyaeva (838-842).
An HPLC method over a Kromasil C18 reversed-phase column with mass spectrometric detection and EtOH:NH4OAc (10:90) mobile phase was developed for quantitative determination of the antitumor drug ormustine in biological fluids. The method enabled detection of both drug isomers, possessed sufficiently high sensitivity and specificity, and was linear over a wide range. The developed method was used to study ormustine pharmacokinetics in rabbits. It was found that the pharmacokinetics of both drug isomers after i.v. injection followed a two-compartment model. The elimination half-lives of ormustine-I were (3.5 ± 0.2) and (109.4 ± 22.2) min for the α- and β-phases, respectively; of ormustine-II, (3.6 ± 0.2) and (79.5 ± 21.7) min, respectively.
Keywords: ormustine; mass spectrometry; pharmacokinetics

Standardization of Gel for Enamel Remineralization by A. L. Golovanenko; E. S. Berezina; E. V. Tret’yakova; I. V. Alekseeva (843-846).
Gel for enamel remineralization was standardized with respect to authenticity, quantitative drug contents, pH level, and microbiological purity using chemical and physicochemical methods modified to account for specific dosage forms. All techniques were tested on laboratory batches of gel, showed well-reproduced results, and could be recommended for inclusion in regulations on the technology and quality control of gel for enamel remineralization.
Keywords: standardization; remineralization; gel; calcium chloride; disubstituted potassium phosphate; sodium fluoride

Optical absorption spectroscopy (OAS) is used in Ukraine mainly for laboratory quality control of medicines. This technique is introduced into regulatory analytical documentation only when the permissible limit of drug substance in the medicine is at least ± 10%. Results from validation tests in two different laboratories of three batches of prednisolone substance were assessed in order to determine the correctness of using OAS for its pharmacopoeial analysis. The practical uncertainty of the OAS spectrophotometric analytical technique for each sample of prednisolone substance analyzed individually in the two laboratories was less than the regulated critical tolerance of ± 3% according to the State Pharmacopoeia of Ukraine. The results allowed the OAS method to be recommended for quality control of prednisolone substance provided the equipment is qualified and the correctness of the results is controlled.
Keywords: prednisolone; optical absorption spectroscopy; spectrophotometric quantitation

Nateglinide, a D-phenylalanine derivative lacking either a sulfonylurea or benzimido moiety, is a novel meal time glucose regulator used for the treatment of type II diabetes. This article examines published analytical methods for the determination of nateglinide in pharmaceuticals and biological samples. The techniques of assay include UV and visible-range spectrophotometry, high performance liquid chromatography (HPLC), high performance thin layer chromatography (HPTLC), micellar liquid chromatography (MLC), micellar electro kinetic chromatography (MEKC) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). However, HPLC with UV-detection is the most widely used technique for the assay of drug both in pharmaceuticals and biological samples. This technique has been also used for studying drug dissolution, separation and determination of enantiomers, impurities and related substances. The assay of nateglinide in blood plasma and serum for studying pharmacokinetics and bioequivalence has principally been carried out with HPLC-UV and LC-MS/MS techniques.
Keywords: nateglinide; analytical methods; pharmaceuticals; biological samples; review

Synthesis, Characterization and Biological Evaluation of Metal Complexes with Water-Soluble Macromolecular Dendritic Ligand by Urvashi Singh; Mohd Nadeem Bukhari; Syed Anayutullah; Hammad Alam; Nikhat Manzoor; Athar Adil Hashmi (868-877).
The development of drug resistant strains of pathogenic fungi despite the availability of a large number of drugs demands for the development of new, more potential drug molecules. Dendrimer-based drug molecules have been comparatively less studied upon recent advancement in this field. In the present work, a new water-soluble dendritic ligand and its copper(II), nickel(II), and cobalt(II) complexes have been synthesized. The ligand, as well as its complexes, were characterized by various physicochemical, analytical, and spectroscopic techniques. On the basis of UV-Vis spectroscopic data, tetragonal geometry was proposed for Cu(II) complex and square planar geometry was established for Co(II) and Ni(II) complexes. The antifungal activities of water-soluble compounds were evaluated using the disk diffusion method, and the minimal inhibitory concentrations (MICs) against Candida albicans ATCC 90028 were determined by the dilution method. The synthesized compounds proved to be fungicidal in comparison to fluconazole, which is fungistatic only; however, these compounds were less active than fluconazole. Hemolysis assays for one of the reported compound showed that it was nontoxic in comparison to fluconazole. Therefore, the proposed compounds can serve as promising leads for the development of new antifungal agents.
Keywords: water-soluble dendritic ligand; disk diffusion method; minimal inhibitory concentration; Candida albicans ATCC 90028; hemolysis