Procedure for setting control for the turnover of new,potentially hazardous psychoactive substances. Detection of metabolites of a new APINAC psychoactive compound in rat urine by gas and liquid chromatography with mass spectrometry detection

The appearance of a new APINAC compound (AKB-57, ACBL(N)-018, adamantan-1-yl-1-pentyl-1H-indazol-3-carboxylate) in the Russian market of psychoactive drugs led to the need in setting measures of state control over its turnover and in solving the problem of categorizing this compound as a potentially hazardous psychoactive substance. To establish these control measures, it was necessary to determine the appropriate chromatographic–mass spectrometric characteristics and to search for its metabolites for their subsequent automated detection. The structure of an APINAC molecule has significant similarity with the molecules of other synthetic cannabinoids. In this paper, primary information on the metabolism of APINAC in the body of rats is presented. A number of putative metabolites, which are the products of hydrolysis of the initial structure and additional monohydroxylation of these products, carbonylation and carboxylation of the lateral N-pentyl chain of indazole-containing metabolites, were detected in rat urine by liquid chromatography–mass spectrometry in the mode of measurement of exact masses and gas chromatography–mass spectrometry. It was found that the formation of glucuronides is characteristic for 1-adamantol and its monohydroxylated metabolite and for the indazole-containing product of hydrolysis of APINAC. The presented mass spectra and retention characteristics of the detected metabolites can help in the detection of these (or similar) compounds in human urine.     

Synthesis,psychotropic and anticancer activity of 2,2‐dimethyl‐5‐[5′‐trialkylgermyl(silyl)‐2′‐hetarylidene]‐1,3‐dioxane‐4,6‐diones and their analogues

A series of 2,2‐dimethyl‐5‐(5′‐R‐hetarylidene)‐1,3‐dioxane‐4,6‐diones has been synthesized for examing a structure–activity relationship. Furyl and thienyl derivatives of Meldrum's acid possess neurotropic activity comprising both depriming and activating components. Comparison of acute toxicity of carbon, silicon and germanium analogues in the furan series of the compounds has demonstrated that the germanium derivative is 11.5 times less toxic than the carbon analogue and four times less toxic than the silicon derivative. 2,2‐Dimethyl‐5‐(5′‐triethylsilyl‐2′‐thenylidene)‐1,3‐dioxane‐4,6‐dione has moderate toxicity with the highest neurotropic and cytotoxic activity Copyright © 2003 John Wiley & Sons, Ltd.     

Integrating 31P DOSY NMR Spectroscopy and Molecular Mechanics as a Powerful Tool for Unraveling the Chemical Structures of Polyoxomolybdate‐Based Amphiphilic Nanohybrids in Aqueous Solution

Novel organic–inorganic hybrids of various sizes were generated by reaction of 1,8‐octanediphosphonic acid (ODP) and (NH₄)₆Mo₇O₂₄ in aqueous solution. The formation of rodlike hybrids with variable numbers of covalently bound ODP and polyoxomolybdate (POM) units can be tuned as a function of increasing (NH₄)₆Mo₇O₂₄ concentration at fixed ODP concentration. The chemical structure of the ODP/POM hybrids was characterized by ¹H, ³¹P, and ⁹⁵Mo NMR spectroscopy. Heteronuclear ³¹P DOSY (diffusion‐ ordered NMR spectroscopy) and molecular mechanics (MM) calculations were applied to determine the size and shape of the nanosized hybrids generated at various ODP/POM ratios. For this purpose, the structures of ODP/POM hybrids with variable numbers of ODP and POM units were optimized by MM and then approximated as cylinder‐shaped objects by using a recently described mathematical algorithm. The thus‐obtained cylinder length and diameter were further used to calculate the expected diffusion coefficients of the ODP/POM hybrids. Comparison of the calculated and experimentally determined diffusion coefficients led to the most probable ODP/POM hybrid length for each sample composition. The ³¹P DOSY results show that the length of the hybrids increases with increasing POM concentration and reaches a maximum corresponding to an average of 8 ODP/7 POM units per chain at a sample composition of 20 mM ODP and 14 mM POM. With excess POM, above the latter concentration, the formation of shorter‐chain hybrids terminated by Mo₇ clusters at one or both ends was evidenced on further increasing the POM concentration. The results demonstrate that the combination of ³¹P DOSY and MM, although virtually unexplored in POM chemistry, is a powerful innovative strategy for the detailed characterization of nanosized organic–inorganic POM‐based hybrids in solution.     

Synthesis,physico‐chemical and biological study of trialkylsiloxyalkyl amine coated iron oxide/oleic acid magnetic nanoparticles for the treatment of cancer

New original water‐soluble magnetic nanoparticles based on natural components, magnetite–oleic acid–biologically active silyl modified alkanolamine, were synthesized. Physico‐chemical characterization, i.e. magnetic properties, concentration of magnetite, size of iron oxide core, of the nanoparticles synthesized and the corresponding magnetic fluids obtained, was carried out. Magnetic fluids were screened for in vitro cytotoxicity concerning human fibrosarcoma (HT‐1080), mouse hepatoma (MG‐22A) monolayer tumour cell lines and normal mouse fibroblasts (NIH 3T3). They possess low or moderate cytotoxic effects, are non‐toxic, exhibit high NO‐induction ability and strongly change tumour cell morphology. Copyright © 2008 John Wiley & Sons, Ltd.     

Synthesis and cytotoxicity of complex compounds of tin, vanadium, and molybdenum with quinolinethiol and its methyl and methoxy derivatives

A series of 8-quinolinethiolates, and 3-methyl-, 4-methyl-, 5-methyl-, 6-methyl-, 7-methyl-, and 6-methoxy-8-quinolinethiolates of tin(II), vanadium(IV), and molybdenum(VI) has been synthesized. Their cytotoxicity on HT-1080 tumor cells (human fibrosarcoma) and MG-22A (mouse hepatoma) cells has been studied. It was established that all of the investigated complexes of 8-quinolinethiol and majority of the complexes of 8-quinolinethiol derivatives possessed very high cytotoxicity towards both cell lines. Their toxicity in relation to mouse embryo fibroblasts NIH 3T3 depended on the position of the substituent in the quinoline ring. Complexes of tin and vanadium with 4-methyl-, 5-methyl-, and 6-methoxy-8-quinolinethiol derivatives were less toxic. 4-Methyl-, 5-methyl-, and 6-methoxy-8-quinolinethiolates of vanadium demonstrated the highest selectivity of cytotoxic action.     

Synthesis and cytotoxicity of phenyl-vinyl derivatives of 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

A series of phenylvinyl derivatives of 4,6,6-trimethyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitriles has been synthesized and their cytotoxic activity towards HT-1080 (human fibrosarcoma) and MG 22A (mouse hepatoma) tumor cells studied. It was found that the 2-nitro-, 2- and 3-chloro, 2-fluoro, and 2-bromophenyl derivatives showed high cytotoxic activity towards both cell lines. The toxicity towards NIH 3T3 normal mouse embryonic fibroblasts depends on the nature and position of the substituent in the phenyl ring. The greatest selectivity of cytotoxic effect was seen in the 2-bromophenyl derivative.     

Synthesis and cytotoxic activity of derivatives of 6<Emphasis Type="Italic">Z</Emphasis>-acetylmethylenepenicillanic acid <Emphasis Type="Italic">tert</Emphasis>-butyl ester

The sulfoxide of 6Z-[2-(methoxyimino)propylidene]penicillanic acid tert-butyl ester and the sulfones of 6Z-[2-(hydroxyimino-, methoxyimino-, benzyloxyimino-, 2-bromo- and 4-bromobenzyloxyimino)-propylidene]penicillanic acid in the syn and anti forms have been synthesized by the condensation of the sulfoxide and sulfone of 6Z-acetylmethylenepenicillanic acid tert-butyl ester with hydroxylamine, methoxyamine, benzyloxyamine, 2-bromo- and 4-bromobenzyloxyamines. The syn and anti isomers of 3Z-(2-methoxyiminopropylidene)-4R-(benzothiazolyl-2-dithio)-2-oxoazetidinyl-1R-(2-propenyl)acetic acid tert-butyl ester were obtained by opening of the thiazolidine ring in 6Z-[2-(methoxy-imino)propylidene]-1-oxopenicillanic acid tert-butyl ester with 2-mercaptobenzothiazole. The 3Z-(2-methoxyiminopropylidene)-4R-(methylsulfonyl)-2-oxoazetidinyl-1-(2-propylidene)acetic acid tert-butyl ester was synthesized by the interaction of 1,8-diazobicyclo[5.4.0]undec-7-ene and methyl iodide with 6Z-[2-(methoxyimino)propylidene]-1,1-dioxopenicillanic acid tert-butyl ester. A dependence of the cytotoxic effect in relation to cancer and normal cells in vitro on the structure of the substituent in position 6 and the syn and anti isomerism of the oxyimino group was established for the synthesized compounds.