Pharmaceutical Chemistry Journal (v.49, #7)

This review presents results on the pharmacokinetic characteristics of osteotropic radiopharmaceuticals (RP) based on polyaminophosphonic acids labeled with various radionuclides. The greatest number of studies cited in the scientific literature address ethylenediaminetetramethylenephosphonic (EDTMP), propylenediaminetetramethylenephosphonic (PDTMP), diethylenetriaminepentakis(methylphosphonic) (PPA), triethylenetetraminohexamethylenephosphonic (TTHMP), 1,4,7,10-tetraazacyclododecan-1,4,7,10-tetramethylenephosphonic (DOTMP) and other acids. RP based on these have high stability in vitro and in vivo, with selective accumulation in bone tissue, and are excreted mainly via the kidneys. This review also presents data on a wide spectrum of radionuclides used to label the various phosphonic acids. These include radionuclides used in radionuclide diagnosis (99mTc, 68Ga) and radionuclide therapy - γ emitters: 153Sm, 188Re, 177Lu, 170Tm, 166Ho, and others, and α emitters: 227Th, 228Ac, and 212Bi.
Keywords: pharmaceutical characteristics; osteotropic radiopharmaceuticals; radionuclides; phosphonic acid derivatives; radionuclide diagnosis; radionuclide therapy; α- and β-emitters

Hepatitis B virus (HBV) is a global threat that killed many human lives. HBV DNA polymerase (HDP) is the key target for antiviral drug treatment. The widely used drug against HBV infection is lamivudine which targets the reverse transcriptase activity of HDP and inhibits the replication of HBV. However, available evidence demonstrated that tyrosine (Y)-methionine (M)-aspartic acid (D)-aspartic acid (D) motif mutations significantly affected the efficacy of lamivudine binding. In particular, M204I mutations affect the drug binding mechanism and cause resistance to lamivudine. Therefore, in the present study we made an attempt to understand the mechanism of lamivudine resistance with the aid of molecular docking and molecular dynamics (MD) approach. The molecular docking results suggest that lamivudine adopts the most promising conformations to the native type HDP by identifying M-204 and Y-203 as a prospective partner for making polar contacts as compared to the mutant type HDP. The MD results showed that the average movements of atoms, especially atoms of the native type HDP– lamivudine complex, were small and displayed fast convergence of energy and charges in geometry. This highlights the stable binding of lamivudine with native type HDP as compared to mutant type HDP. The R2 and RMSF analysis certainly indicates conformational changes in the HDP structure due to M204I mutation. Furthermore the hydrogen bond (H-bond) analysis from the MD study showed that there is decreased number of intermolecular H-bonds in mutant HDP – lamivudine complex as compared to that in native type HDP – lamivudine complex. Overall, our study certainly will pave way to develop new drugs against the drug resistant mutations (M204I) of HBV.
Keywords: HBV DNA polymerase; drug resistance; molecular docking; molecular dynamics simulation

Synthesis of GK-2, a Dimeric Dipeptide Nerve Growth Factor Mimetic and Potential Neuroprotective Agent by N. M. Sazonova; A. V. Tarasyuk; D. V. Kurilov; S. V. Pomogaibo; T. A. Gudasheva (439-448).
A series of dipeptide mimetics of nerve growth factor were synthesized, one of which, bis-(monosuccinyl-Lglutamyl-L-lysine) hexamethylenediamide (GK-2), constructed on the basis of the β-turn of its fourth loop, was selected for development as a potential neuroprotective drug. This study describes the first phase in the creation of a technology for producing GK-2 – selection of the optimum synthesis scheme. Two nine-stage synthesis schemes were assessed, consisting of lengthening the peptide chain from the N or C terminal. Condensation in both cases was performed using N-hydroxysuccinimide esters. Both schemes yielded product with identical optical and diastereomeric purity, not requiring complex purification and involving similar time input, though the scheme growing the peptide chain from the C terminal was 1.2 times more economical in terms of reagent costs per kg of product and was selected as the main method for developing the laboratory methodology.
Keywords: mimetic; dipeptide; peptide synthesis; NGF

Synthesis and Antiviral Activity of Adamantylpeptides Against Hepatitis C Virus by V. A. Shibnev; T. M. Garaev; P. G. Deryabin; M. P. Finogenova; D. V. Mishin (449-454).
New adamantane derivatives with short peptides were synthesized and their in vitro antiviral activity against hepatitis C virus (HCV) was studied. Experiments in pig embryo kidney cells (PEKC) showed that 1-(1-adamantyl)ethylamine derivatives with tri- and tetrapeptide residues were able to suppress HCV replication. Furthermore, this class of compounds was shown to have direct actions on the infective properties of hepatitis C virions (virucidal activity).
Keywords: adamantane derivatives; peptides; p7 channel; remantadine; hepatitis C; cell cultures; antiviral activity

Synthesis, Stability, and Antimicrobial Activity of Diiodobromides of 1H,2H,3H,4H-Pyrido-[4,3-d]Pyrimidinium Derivatives by Yu. A. Kirsanova; M. S. Chernov’yants; I. V. Burykin; O. A. Podoinitsyna (455-458).
Iodination of chloroform solutions of the bromides of 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium with a threefold excess of iodine was performed to synthesize the diiodobromides of the corresponding organic cations. The composition and structure of these compounds were confirmed by UV and 1H NMR spectroscopic and potentiometric titration methods. Values for the stability constant lgβ (3.05 – 4.68) allowed active iodine concentrations at the bactericidal level to be produced in solutions of 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium diiodobromides. The minimum inhibitory concentrations (MIC) of 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium diiodobromides against E. coli were 1.0 ± 0.25 mg/ml.
Keywords: bromides and diiodobromides of 1H,2H,3H,4H-pyrido[4,3-d]pyrimidinium derivatives; stability of iodohalogenides; antimicrobial activity

The acute toxicity, hypoglycemic, antihypoxic, and immunopharmacological activities and the effects on behavior and memory of bis[3-(4-chlorophenyl)-1-(4-methylphenyl)carboxamido-1,3-propandionato]oxovanadium were studied in comparison with starting ligands vanadium sulfate and metformin. The compound had low toxicity, while hypoglycemic and immunomodulatory activity were greater than those of the reference substance and the initial synthesis products.
Keywords: bis[3-(4-chlorophenyl)-1-(4-methylphenyl)carboxamido-1,3-propandionato]oxovanadium; hypoglycemic and immunopharmacological activities

Anti-Inflammatory Activity of New Series of 1,4-Dihydropyridine Derivatives by A. Idhayadhulla; R. Surendra Kumar; A. Jamal Abdul Nasser; S. Kavimani; S. Indhumathy (463-466).
Aseries of 1,4-dihydropyridine derivatives (1a – 1g) were prepared by multicomponent condensation reaction of ethylchloroacetate, 4-substituted benzaldehyde, and ammonium hydroxide as starting materials. A new series of dihydrazine carbothioamides (2a – 2g) were prepared by condensation of compounds 1a – 1g with thiosemicarbazide. The structures of synthesized compounds were confirmed by IR and 1H-NMR spectroscopy and elemental analysis. Compounds 1a – g and 2a – 2g were tested for anti-inflammatory activity on Swiss albino rats.
Keywords: 1,4-dihydropyridine; thiosemicarzide; condensation; anti-inflammatory activity

We report here the first identification and assay of several phenolic compounds in the dwarf Labrador tea growing in various areas of the Yamalo-Nenets Autonomous District, using HPLC. Nine phenolic compounds were identified, these being flavonoids, phenolcarbonic acids, catechols, and tannins: tannin, epicatechin, gallic, chlorogenic, and caffeic acids, and the flavonoids vitexin, rutin, dihydroquercetin, and luteolin-7-glycoside. Investigations of the dwarf Labrador tea may be of interest for its further study with the aim of broadening the native raw materials base for this medicinal material. The presence of tannin, gallic acid, and vitexin in significant quantities in this material suggests that dwarf Labrador tea shoots may have a wide spectrum of pharmacological activity.
Keywords: dwarf Labrador tea; raw material; phenolic compounds; vitexin; gallic acid

Comparative Analysis of the Hypolipidemic Activity of Extracts From Sacred Lotus by E. I. Kondratenko; N. A. Lomteva; M. A. Samotrueva; M. V. Mizhitova (470-472).
We present here the results of experimental studies demonstrating the marked hypolipidemic activity of sacred lotus extracts, decreasing blood total cholesterol, triglyceride, and total lipid levels. An extract of sacred lotus petals had the greatest hypolipidemic activity.
Keywords: extracts of leaves; petals; seeds; and seed bolls of the sacred lotus; hypolipidemic activity

Anti-complement activity is a measure of the specific safety of human immunoglobulins characterizing one of the unwanted effect - spontaneous activation of the complement system. In compliance with the specifications of the European Pharmacopeia and WHO recommendations, the anti-complement activity of human immunoglobulin preparations must not be greater than 50%, which corresponds to a maximum of 1 CH50/mg of immunoglobulin. The measurement method was based on the ability of human immunoglobulins to produce “nonspecific” (in the absence of an antigen-antibody complex) binding of complement, preventing lysis of sensitized sheep red blood cells. We present here the results of analysis of the critical parameters of the method for measuring anti-complement activity, along with assessment of existing methodological approaches to its optimization. We report experimental studies of the effects of components of the hemolytic system and complement in guinea pigs on the results of measurements of anti-complement activity. The optimum conditions for the method of measuring the anti-complement activity of human immunoglobulins are based in evidence and the anti-complement properties of human immunoglobulin preparations for intravenous use of Russian origin are evaluated.
Keywords: human immunoglobulin; anti-complement activity; specific safety; standard immunoglobulin

Comparison of the Bioavailabilities of Two Medicinal Formulations of Fampridine in Healthy Volunteers by V. G. Belolipetskaya; V. S. Arnautov; E. K. Zakharova; D. V. Reikhart; A. V. Belostotskii (477-480).
The bioavailabilities of two medicinal formulations of fampridine – fampridine slow-release tablets, 10 mg (study agent, OAO Valenta Farmatsevtika, Russia) and Fampyra slow-release tablets, 10 mg (reference agent, Biogen Idec Ltd., UK) were compared in an open, randomized, crossover study using single 10-mg doses. Mean (± SD) C max was 27.28 ± 4.33 ng/ml for reference agent and 26.63 ± 3.44 ng/ml for study agent. Mean AUC values were 302.56 ± 56.23 and 300.57 ± 55.24 ng.h/ml respectively. The 90% confidence interval for geometrical mean C max and AUC were in the ranges 91 – 105% for C max and 90 – 109% for AUC. The boundaries of the 90% confidence intervals were in the acceptable range (80 – 125%), complying with the requirements for confirming the bioequivalence of the agents being compared.
Keywords: fampridine; bioavailability; C max ; AUC

Preparation and Investigation of Tabletted Medicinal Formulations of a Solid Dispersion of Rutin by I. I. Krasnyuk Jr; I. V. Koval’skii; O. I. Nikulina; A. V. Belyatskaya; I. I. Krasnyuk; Yu. Ya. Kharitonov; V. V. Grikh; L. A. Korol’; Yu. A. Obidchenko; A. N. Vorob’ev (481-485).
Asolid dispersion of rutin based on polyvinylpyrrolidone had greater solubility than rutin substance, which is valuable for creating effective formulations based on this material. We describe here the preparation of tableted medicinal formulations of a solid dispersion of rutin prepared by direct pressing and moist granulation. A comparative analysis of the resulting granulates and tablets in terms of the main physical-technical characteristics is presented.
Keywords: rutin; rutin aglycone; properties; mechanism of action

An efficient synthesis of 16β-methyl-pregn-4,9(11)-diene-17α-ol-3,20-dione from 9α-hydroxyandrostenedione via its ∆9-analog has been developed. Structure of the product and its intermediates were examined by spectral methods including IR spectroscopy, mass spectrometry, and 1D and 2D NMR techniques.
Keywords: synthesis; 16β-methyl-pregn-4,9(11)-diene-17α-ol-3,20-dione

Changes in Approaches to the Normalization of Heavy Metal Contents in Medicinal Herbs and Herbal Medicines (Review) by N. E. Kuz’mina; V. M. Shchukin; E. Yu. Severinova; V. A. Yashkir; V. A. Merkulov (490-494).
Analysis of normative documents identified a tendency to eliminate differences in approaches to the normalization of heavy metals contents in medicinal substances, medicinal herbs, and herbal medicines. The current main principle of the normalization of heavy metals is the principle of selective assay.
Keywords: heavy metals; normalization; acceptable limits; medicinal herbs; herbal medicines