Pharmaceutical Chemistry Journal (v.48, #6)

Pharmacokinetic Study of the New Diagnostic Radiopharmaceutical 99mTc-Pentaphosphonic Acid in Rats with an Experimental Bone-Fracture Model by V. M. Petriev; V. K. Tishchenko; O. V. Siruk; O. A. Smoryzanova; V. G. Skvortsov (357-362).
The pharmacokinetic properties of a bone-seeking radiopharmaceutical based on pentaphosphonic acid labeled with technetium-99m (99mTc-PPA) were investigated. The experiments were performed in healthy rats and in rats with a femoral bone-fracture (BF) model. The radiopharmaceutical was injected into a tail vein 14 days after the fracture. 99mTc-PPAshowed good stability in vivo because it accumulated in the thyroid less than unlabeled 99mTc. The maximum accumulation of 99mTc-PPA was found in bones tissue, where it reached 1.48 ±0.19% of injected dose per gram of tissue at 1 h after injection. The drug exhibited rapid blood clearance, showed minimum uptake into soft organs and tissues, and was excreted mainly via renal pathways. The presence of femoral BF significantly changed the biodistribution of 99mTc-PPAin soft organs and tissues. The 99mTc-PPAcontent in BF was 1.9 – 2.5 times higher than in healthy femur and 2 – 3 times higher than in skeleton. The concentration of 99mTc-PPAin other soft organs and tissues of rats with bone lesion was lower than in organs and tissues of healthy rats. The maximum BF-to-blood and BF-to-muscle ratios were 184.8 ±14.1 and 415.4 ±59.5, respectively, 3 h after injection. The results showed that 99mTc-PPAhad favorable properties for diagnosing bone-tissue metastases.
Keywords: pharmacokinetic study; radiopharmaceutical; 99mTc-pentaphosphonic acid; experimental bonefracture model; technetium; rats; diagnostics; bone-tissue metastases

Synthesis and Cytostatic Activity of some Pregna-D′-Pentaranes on HeLa Cell Culture by A. V. Semeikin; T. A. Fedotcheva; I. S. Levina; L. E. Kulikova; I. V. Zavarzin; D. A. Tikhonov; E. N. Kareva; N. L. Shimanovskii (363-367).
The effects of nine new pregnane steroids containing substituents in the 16α,17α- and/or 3-, 6-, and 19-positions of the steroid framework on the viability of HeLa cervical cancer cells were studied. It was shown that the 6-oximes of 3-keto- and 3-hydroxy-4-dehydrosteroids with a 16α,17α-cyclohexane substituent and 3-keto-4-dehydrosteroids with a 16α,17α-phenylcyclopropane substituent reduced the viability of the cell culture. Compound K1047 had the highest cytostatic effect and was promising as a potential hormonal antitumor agent.
Keywords: pregna-D′-pentaranes; progesterone; HeLa; MTT

Amides that cyclized into 2-substituted 3H-spiro[benzo(h)quinazoline-5,1′-cyclohexane]-4(6H)-ones were prepared by reaction of 4′-amino-1′H-spiro[cyclohexane-1,2′-naphthalene]-3′-nitrile with carboxylic acid chlorides. Substitution of the benzoquinazolines by alcoholates, secondary amines, and thiolates was investigated. Thus,2-(3-chloropropyl)-3H-spiro[benzo[h]quinazoline-5,1′-cyclohexane]-4(6H)-one underwent intramolecular cyclization to form 10,11-dihydro-5H-spiro[benzo[h]pyrrolo[2,1-b]quinazoline-6,1′-cyclohexane]- 7(9H)-one whereas 2-chloromethyl-3H-spiro[benzo[h]quinazoline-5,1′-cyclohexane]-4(6H)-one formed substitution products. The influence of the synthesized compounds on brain monoamine oxidase activity was studied in vitro. It was found that the majority of the compounds inhibited deamination of 5-HT. The antitumor activity of the compounds was studied using two grafted murine tumor models, i.e., Ehrlich ascites carcinoma and sarcoma 180. Some of the investigated compounds suppressed tumor growth by 50 – 56%.
Keywords: benzo[h]quinazoline; spiro; cyclization; 5-HT deamination; antitumor activity

Antiproliferative Activity of Tubuloclustin and its Steroid Analogs by O. N. Zefirova; E. V. Nurieva; Ya. S. Glazkova; N. A. Zefirov; A. V. Mamaeva; B. Wobith; V. I. Romanenko; N. A. Lesnaya; E. M. Treshchalina; S. A. Kuznetsov (373-378).
Daily administration of tubuloclustin (1 mg/kg, 5 d, i.p.) to BDF1 mice with i.p. transplanted P388 leukemia extended statistically significantly by 45% their life spans compared with those of untreated controls (17 vs. 11.7 ± 3 d). The possibility in principle of preparing 2-methoxyestradiol analogs with a linker bonded through a steroid C6 ester was demonstrated. However, the resulting conjugates IIa and IIb were unstable with respect to a strong tendency for elimination from the C6–C7 bond. This may have been the reason for their low cytotoxicity in the MTT assay on A549 cell culture (IC50 > 10 μM). It was concluded that conjugates of higher stability must be synthesized as potential antitumor agents.
Keywords: colchicine derivatives; adamantane; tubulin; tubuloclustin; P388 leukemia; antitumor activity; 2-methoxyestradiol; A549 human lung carcinoma cell line; cytotoxicity

Antiproliferative and antimicrobial activity of methyl-6-amino-3-acyl-4-aryl-5-cyano-4H-pyran-2-carboxylates and their analogs that were synthesized from methyl-2,4-dioxobutanoates was studied. Studies of their antiproliferative activity at the USA National Cancer Institute under the program NCI 60 Cell One-Dose Screen found that methyl-6-amino-5-cyano-4-(furan-2-yl)-3-(3-methoxybenzoyl)-4H-pyran-2-carboxylate had the highest activity, greater than those of busulfan and cisplatin. Methyl-6-amino-3-acetyl-4-phenyl-5-cyano-4H-pyran-2-carboxylate had antimicrobial activity that was comparable with that of chloramine.
Keywords: pyrans; decyclization; antitumor activity; methyl 2,4-dioxobutanoates; tumor cells; inhibition

Synthesis and Tuberculostatic Activity of Some 1,2,4-Triazines by E. V. Shchegol’kov; O. G. Khudina; A. E. Ivanova; Ya. V. Burgart; E. V. Sadchikova; M. A. Kravchenko; V. I. Saloutin (383-386).
The antituberculosis activity of dihydrotriazolo[5,1-c][1,2,4]triazines, dihydropyrazolo[5,1-c][1,2,4]triazines, dihydroimidazolo[5,1-c][1,2,4]triazines, and dihydrotetrazolo[5,1-c][1,2,4]triazines was studied. A synthetic method for convenient synthons, 3-amino-1,2,4-triazines, was proposed. Their tuberculostatic activity was investigated.
Keywords: antituberculosis activity; 1,2,4-triazines; synthesis

Biochemical and Morphological Changes in White Rats After Intragastric Injecton of a Synthetic Nanobiocomposite Based on Silver Nanoparticles and Arabinogalactan by M. A. Novikov; E. A. Titov; L. M. Sosedova; L. A. Ostroukhova; N. N. Trofimova; V. A. Babkin (387-390).
Results from the synthesis and biological testing of a new nanobiocomposite containing silver (Ag) nanoparticles encapsulated in the natural biologically active polymer arabinogalactan were presented. The physicochemical properties of the water-soluble Ag-containing polymeric nanocomposite were described. It was found that the new nanocomposite upon intragastric injection to white rats activated the antioxidant system, caused slight changes in brain and liver tissues, and produced biochemical shifts characteristic of compensatory—adaptive stress mechanisms.
Keywords: nanocomposite; arabinogalactan; Ag nanoparticles; experimental studies; subacute injection; white rats; organ tissue morphology

Molecular Complexes of ivy and Licorice Triterpene Glycosides with Doxorubicin by L. A. Yakovishin; V. I. Grishkovets; A. V. Klimenko; A. D. Degtyar; E. B. Kuchmenko (391-394).
The complexation of doxorubicin hydrochloride with the triterpene glycosides α-hederin [hederagenin 3-O-α-L-rhamnopyranosyl-(1→2)-O-α-L-arabinopyranoside], hederasaponin C [hederagenin 3-O-α-Lrhamnopyranosyl-(1→2)-O-α-L-arabinopyranosyl-28-O-α-L-rhamnopyranosyl-(1→4)-O-β-D-glucopyrano syl-(1→6)-O-β-D-glucopyranoside), and glycyram (monoammonium glycyrrhizate) in aqueous solutions at pH 7.2 was investigated using spectrophotometry. These glycosides formed 1:1 complexes with doxorubicin. The complex stability constants were determined.
Keywords: triterpene glycosides; α-hederin; hederasaponin C; ammonium glycyrrhizate; glycyram; doxorubicin; molecular complex; spectrophotometry

Extraction of Sr-82, Raw Material for Radiopharmaceutical Production by A. V. Dunin; N. A. Nerozin; N. R. Togaeva; S. V. Khamyanov; V. V. Shapovalov (395-397).
A method for producing strontium-82, which is used in nuclear medicine for the preparation of rubidium-82 generators that are used in positron-emission tomography (PET) diagnostics of cardiovascular diseases, was described. The method consisted of irradiation of natural rubidium metal in a proton beam of energies from 40 to 100 MeV followed by radiochemical extraction of the produced strontium-82. The method enabled the irradiated target to be processed safely with simultaneous disposal of the rubidium metal and will be used for strontium-82 production at IPPE (Obninsk).
Keywords: nuclear medicine; strontium-82; rubidium-82; extraction chromatography; ion exchange

Improved Method for Isolating Temozolomide from its Dimethylsulfoxide Solvate by Yu. Yu. Kozyr’kov; E. A. Matyushenkov; S. A. Belyaev (398-401).
A simple method for isolating temozolomide, which is used to treat several types of malignant tumors, from its dimethylsulfoxide (DMSO) solvate was investigated. The method consisted of treating temozolomide DMSO solvate with a refluxing Me2CO:H2 O mixture. It was found that decreasing the H2O content in the mixture and reducing the reflux time improved the purity of the final product. The best result was obtained by refluxing the sample in anhydrous Me2CO. The reproducibility of the proposed method was demonstrated. It was established that the size of temozolomide crystals obtained by this method was much smaller than after recrystallization from aqueous Me2CO.
Keywords: temozolomide; dimethylsulfoxide solvate

In this study, a chemometrics approach has been used to optimize the particle size of quercetin-containing nanoemulsions prepared with spontaneous emulsification method. The experiments were performed according to the Box – Behnken experimental design, one of the most suitable experimental designs for modeling studies. The effect of three experimental parameters on the droplet size was studied using multivariate analysis. The factors studied (and their variation levels) were the concentration of lecithin in aqueous phase (0.7 – 2% w/w), the concentration of tween-80 in aqueous phase (2 – 8% w/w), and sonication time (10 – 60 minutes). In each step of experimental design, the aqueous phase was added to the organic phase including lecithin, tween-80, and quercetin in ethanol solvent. Then, the mixture was treated in ultrasonic bath for 15 min and organic solvent was removed by rotary evaporator. The droplet size was measured by a Zetasizer instrument. After determining the average particle size for each experimental run according to experimental design, modeling of this parameter was conducted in terms of experimental factors by using multiple linear regressions with SPSS software. The obtained regression model was characterized by both its descriptive and predictive ability (R 2 =0.999, standard error SE =4.205, and F =245.698) and allowed the preparation of quercetin nanoemulsions in a desired range.
Keywords: quercetin; nanoemulsion; spontaneous emulsification; Box – Behnken design; lecithin

Analytical Method Development for Tablets of the New Kappa-Opioid Agonist RU-1205 by A. A. Illarionov; L. N. Grushevskaya; L. M. Gaevaya; M. E. Dudenkova; N. I. Avdyunina; B. M. Pyatin; K. V. Alekseev; E. V. Blynskaya; I. V. Bogunova (408-413).
An analytical method for tablets of the new imidazobenzimidazole kappa-opioid agonist RU-1205 was developed. The principal pharmacopoeial parameters of tablet quality were studied. The contents of impurities and RU-1205 in the tablets were assayed quantitatively using HPLC. A method for determining the dose uniformity using UV spectrophotometry was developed. Procedures were proposed for determining the authenticity and dissolution profile of RU-1205 tablets.
Keywords: RU-1205; tablets; pharmaceutical analysis; analytical method; HPLC; UV spectrophotometry; impurities; quantitative determination; dose uniformity; dissolution test

Quantative Determination of the New Glutamic Acid Derivative Glutaron in Biological Samples by L. A. Smirnova; A. F. Ryabukha; K. A. Kuznetsov; E. A. Suchkov; V. N. Perfilova; I. N. Tyurenkov (414-416).
An HPLC method for quantitative determination of glutaron was developed in order to perform a pharmacokinetic analysis. The method was highly sensitive and selective and could be used for determination in biological samples. The sample preparation method was optimized and did not significantly affect the average measurement error of the HPLC quantitative determination.
Keywords: HPLC; glutaron; quantitative determination