Pharmaceutical Chemistry Journal (v.47, #5)

Effect of Cyclic Hydroxamic Acids Derived from Glycine and D,L-Alanine on Activity of Ca2+, Mg2+-ATPase Hydrolases of Sarcoplasmic Reticulum and Cyclic Guanosine Monophosphate Phosphodiesterase by L. V. Tat’yanenko; N. P. Konovalova; O. V. Dobrokhotova; I. Yu. Pikhteleva; D. V. Mishchenko; B. S. Fedorov; I. V. Vystorop (235-238).
The effects of cyclic hydroxamic acids (CHAs) derived from glycine and D,L-alanine on the enzymatic activity of Ca2+,Mg2+-ATPase from sarcoplasmic reticulum (Ca2+,Mg2+-ATPase SR) and cyclic guanosine monophosphate phosphodiesterase (PDEcGMP) were investigated. CHAs I (C5H10N2O2), II (C6H12N2O2), III (C8H15N3O2), IV (C9H17N3O2), V (C11H21N3O2), and VI (C12H23N3O2) were modulators of Ca2+,Mg2+-ATPase SR enzyme activity. Compounds I-VI decoupled to various extents the hydrolytic and transport functions of Ca2+,Mg2+-ATPase SR, disrupting the ratio of intra- and extracellular Ca2+ ions. This affected the adhesion of metastatic cells to capillary endothelium. Compounds IV and VI had the highest metastasis inhibition indices (MII%) for B-16 melanoma of 33 and 81%, respectively. This correlated with a decreased Ca2+ transmembrane transfer coefficient into SR vesicles of 0.75 for IV and 0.5 for VI compared with a [Ca2+]/[ATP] ratio in the control of 1.4. CHAs I-VI did not affect the functioning of PDEcGMP. The results enabled potential antimetastatic drugs in the CHA series to be predicted.
Keywords: Ca2+-activating-Mg2+-independent ATPase of sarcoplasmic reticulum; cGMP phosphodiesterase; inhibition constant; ATP hydrolysis; active Ca2+ transport; cyclic hydroxamic acids

Synthesis and Anxiosedative and Antidepressant Properties of α-[4-Oxoquinazolin-3(4H)-yl]carboxylic Acid Anilides by I. N. Tyurenkov; A. A. Ozerov; E. A. Solodunova; Yu. V. Archakova; E. N. Shmatova; K. T. Sampieva (239-242).
A series of new quinazoline acetanilide derivatives were synthesized by direct alkylation of quinazoline-4(3H)-one with α-chlorocarboxylic acid anilides. The anxiosedative and antidepressant properties of 10 original derivatives of α-[4-oxoquinazolin-3(4H)-yl]carboxylic acids were studied. It was established that N-(4-methoxyphenyl)-2-[4-oxo-3(4H)-quinazoline]acetamide and 3-[2-oxo-2-(4-phenyl-1-piperazinyl)-ethyl]quinazoline-4(3H)-one exhibited pronounced anxiolytic, antiphobic, and antidepressant activity and were promising candidates for further studies of their psychotropic properties.
Keywords: quinazoline derivatives; anxiolytic and antidepressant activity

Synthesis of the potential dipeptide neuroleptic dilept and its active metabolite by E. A. Kuznetsova; N. M. Sazonova; S. V. Nikitin; L. A. Zhmurenko; T. A. Gudasheva (243-246).
The new potential neuroleptic drug dilept (N-caproyl-L-prolyl-L-tyrosine methyl ester) was created. A four-step scalable synthetic method for dilept that enabled the product to be obtained in 52% yield without racemization was presented. The process included preparation of caproic acid chloride using thionylchloride, Schotten–Baumann acylation of L-proline by the obtained acid chloride, esterification of L-tyrosine in MeOH in the presence of thionylchloride, and synthesis of the methyl ester of N-caproyl-L-prolyl-L-tyrosine by the mixed anhydride method using isobutylchloroformate in DMF. The active metabolite of dilept (N-caproyl-L-prolyl-L-tyrosine) was synthesized and characterized by physicochemical methods.
Keywords: neuroleptic dilept; neurotensin; dipeptide; metabolite

Synthesis and broncholytic activity of N-alkylpiperazino-substituted uracil and xanthine by S. A. Meshcheryakova; V. A. Kataev; R. A. Galimova (247-250).
8,10-Dimethylpiperazino[1,2-e]xanthine was synthesized by intramolecular cyclization of 1,3-dimethyl-5-nitroso-6-piperazinouracil followed by treatment with HCl and NaOH. N-alkylation of 1,3-dimethyl-6-piperazinouracil and 8,10-dimethylpiperazino[1,2-e]xanthine with oxiranes and benzoylchloride yielded N-alkylpiperazino-substituted derivatives. The structures of the synthesized compounds were confirmed by IR and PMR spectroscopic data. It was established that the synthesized compounds exhibited broncholytic activity.
Keywords: N-alkylation; piperazino[1,2-e]xanthine; 6-piperazinouracil; benzoylchloride; oxiranes; broncholytic activity

Pharmacokinetics of 188Re-labeled pentaphosphonic acid in rats with experimental bone callosity by V. K. Shiryaeva; V. M. Petriev; O. A. Smoryzanova; V. G. Skvortsov (251-256).
The influence of modeled femur callosity on the biodistribution of 188Re-labeled pentaphosphonic acid (188Re-PPA) in rats was studied. The radiopharmaceutical was injected into a tail vein 14 d after fracture. It was established that the presence of bone callosity had a significant influence on 188Re-PPAbiodistribution in soft tissues and organs. 188Re-PPA showed good stability in vivo because its uptake by thyroid gland was low compared to that of unbound 188Re. The maximum activity levels were observed in bone callosity (up to 1%/g), bone tissue in general, liver, and kidneys. The 188Re-PPAconcentration in bone tissue of rats with bone callosity was 2.4 – 10.6 times lower than that in bone tissue of intact animals. The maximum 188Re-PPAactivity in bone tissue of intact rats and those with bone callosity 1 h after i.v. injection was 2.12 and 0.42%/g, respectively. The coefficients of differential accumulation (CDA) of drug activity in bone callosity relative to soft tissues and organs were calculated. 188Re-PPAuptake by bone lesion was greater than that by normal bone tissue. The CDA values enabled the accumulation dynamics and elimination rate of 188Re-PPA from soft tissues and organs to be compared with those from bone fracture. In addition, the CDA values allowed the optimum period for carrying out skeletal scintigraphic studies using a gamma camera to be determined. In conclusion, 188Re-PPA had appropriate biological characteristics for use as a bone-pain pallation agent for the treatment of bone metastases.
Keywords: pentaphosphonic acid; 188Re; pharmacokinetics

Synthesis and antibacterial activity of N-amino-derivatives of condensed pyridines by E. G. Paronikyan; Sh. F. Hakobyan; A. S. Noravyan; G. Hajos; Sh. Sh. Dashyan; R. V. Paronikyan; G. M. Stepanyan (257-260).
A method based on condensed 4-cyanopyridinethiones using O-tosylhydroxylamine as the aminating agent was developed for preparing tosylates of N-amino-derivatives of pyrano[3,4-c]pyridines; 5,6,7,8-tetrahydroisoquinolines; and cyclopenta[c]pyridines. The antibacterial activity of the synthesized compounds was assessed.
Keywords: N-aminopyridines; tosylates; pyrano[3,4-c]pyridines; 5,6,7,8-tetrahydroisoquinolines; cyclopenta[c]pyridines; antibacterial activity

Mutagenic and antimitotic activity of the immunomodulatory drug tubosan by B. S. Kibrik; I. M. Prokhorova; D. S. Pesnya (261-263).
The mutagenic and antimitotic activities of the standard antituberculosis drug isoniazid and the immunomodulatory drug tubosan were compared using the Allium test, which took into account the frequency of chromosome aberrations, chromosome lagging, and micronuclei and allowed the mitotic and phase indices to be determined. It was established that isoniazid at concentrations 10, 60, and 120 mg/L inhibited fully the mitotic activity in tissues (for which the mitotic index was zero), implying that isoniazid exhibited very strong mitotoxic activity. The micronucleus test showed that the mutagenic activity of isoniazid increased with increasing concentration. The micronuclei induced by isoniazid were formed as a result of nuclear budding into the interphase. Isoniazid at a concentration of 300 mg/L led to the death of the test object. Tubosan at concentrations 60, 120, 800, and 1200 mg/L showed neither mutagenic nor antimitotic effects. The phase indices were also the same as those in the control. Thus, tubosan did not exhibit genotoxicity and could be classified as a genetically safe drug in the studied concentration range.
Keywords: tubosan; isoniazid; mitotic index; chromosome aberration; micronuclei; Allium test

Data published in 1999 – 2011 on the synthesis and chemical properties of adamantyl-containing nucleic bases and related compounds are reviewed, systematized, and analyzed. Adamantyl-containing heterocyclic compounds, which have received much attention in attempts to create highly effective and selective drugs that were described in previous reviews devoted to heteryladamantanes, occupy a special place in adamantane chemistry. The number of publications devoted to the synthesis and characterization of adamantyl-containing nucleic bases was small and restricted mostly to derivatives containing unsubstituted adamantane. The ability to overcome this limitation was realized only in the last decade. Available data on the biological activity of synthesized compounds indicate good prospects for research in this direction.
Keywords: nucleic bases; adamantane derivatives

Water–Hexylene Glycol System as a Potential Medicinal Base by E. P. Bezuglaya; A. N. Lyapunova; A. P. Krasnoperova (281-286).
Variation of the surface tension in a series of water–hexylene glycol (HG) two-component solvents was studied. It was shown that HG with its low value of hydrophilic–lipophilic balance (HLB) decreased significantly the surface tension, which depended on the HG concentration and the structure of the mixed solvent. The kinematic viscosity of a series of two-component water–HG solvents was studied as a function of composition and temperature. Quasi-thermodynamic characteristics of the activation of viscous flow, Panchenkov bond energy, and intermolecular interaction energy were calculated as a function of solvent composition. Structural features of water–HG mixed solvents, in particular, destruction of the water structure upon adding HG, were demonstrated. It was noted that the bond energy in water–HG associates was greater than that of water–water and HG–HG. The surfactant properties of polysorbate 20 in binary water–HG solvents, which had a mixed solvent structure with the HG structure dominating, were shown to be lost. It was suggested that HG influenced the stability of heterogeneous dispersed systems with a liquid dispersed medium depending on the concentration and structure of the dispersed medium. Possibilities of using HG in the technology of liquid and soft solid medicinal forms were discussed.
Keywords: hexylene glycol; thermodynamics

Phagocytic Activity of N-Vinylpyrrolidone and 2-Methyl-5-vinylpyridine Copolymers by S. A. Kedik; A. V. Panov; I. V. Sakaeva; Yu. V. Kochkina (Cherta); E. I. Yartsev (287-288).
A copolymer of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine was shown to increase the phagocytic activity of macrophages. A tendency of the fraction of phagocytic cells, the phagocytic index, and the index of phagocytosis completeness to increase was observed after its administration.
Keywords: copolymer of N-vinylpyrrolidone and 2-methyl-5-vinylpyridine; phagocytic activity