Drug discovery based on the structure of FKBP12: Design, synthesis and evaluation of L-1,4-thiazane-3-carboxylic acid derivatives as neuroimmunophilin ligands

By choosing neuroimmunophilin FKBP12 as a therapeutical target, we have attempted to discover a new structural drug for treating neurodegenerative disease. This drug should possess neurotrophic activity and not affect the immune system. Based on the crystal structure of FKBP12, FK506 and Calcineurin complex, a series of small organic molecules were designed. These molecules were to have the ability of binding to FKBP12 in a virtual screening. By using a solution parallel synthetic method, these compounds were synthesized. The neuroprotective and neuroregenerative activities of these compounds were evaluated by binding assays, PC12 cells survival and neurite outgrowth model, chick dorsal root ganglion cultures (DRG) and 6-OHDA lesioned mice sympathetic nerve endings model. The evaluation results of these compounds showed that compound N308 has great promise as a candidate for a neuroprotective and neuroregenerative agent.     

Ellagic acid derivatives from the stem bark of <Emphasis Type="Italic">Dipentodon sinicus</Emphasis>

Ellagic acid derivatives were isolated from Dipentodon sinicus and their structures were identified as 3,3′,4′-tri-O-methylellagic acid (1), 3,3′-di-O-methylellagic acid (2), 4,4′-di-O-methylellagic acid (3), 3,3′-di-O-methylellagic acid-4′-O-α-L-rhamnopyranoside (4), 3,3′,4′-tri-O-methylellagic acid-4′-O-β-D-glucopyranoside (5), 3,3′-di-O-methylellagic acid-4′-O-β-D-glucopyranoside (6), and ellagic acid (7). All the compounds were isolated for the first time from the title plant. Published in Khimiya Prirodnykh Soedinenii, No. 2, pp. 106–107, March–April, 2007.     

Synthesis of 4<Emphasis Type="Italic">E</Emphasis>,7<Emphasis Type="Italic">Z</Emphasis>-tridecadien-1-ylacetate,a component of the <Emphasis Type="Italic">Phthorimaea opercucella</Emphasis> sex pheromone

A new synthetic approach to 4E,7Z-tridecadien-1-ylacetate, a component of the Phthorimaea opercucella (Zeller) potato moth sex pheromone, was developed using a highly stereoselective Claisen rearrangement and Wittig reaction. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 235–236, May–June, 2007.     

Synthesis of isomeric 2-oxazolidinones from (1<Emphasis Type="Italic">R</Emphasis>,2<Emphasis Type="Italic">R</Emphasis>)-and (1<Emphasis Type="Italic">S</Emphasis>,2<Emphasis Type="Italic">S</Emphasis>)-2-amino-1-(4-nitrophenyl)-1,3-propanediols

A synthesis is reported for (4R,5R)-and (4S,5S)-4-hydroxymethyl-5-(4-nitrophenyl)oxazolidin-2-ones and (1′R,4R)-and (1′S,4S)-4-[hydroxy(4-nitrophenyl)methyl]oxazolidin-2-ones from (1R,2R)-and (1S,2S)-2-amino-1-(4-nitrophenyl)-1,3-propanediols. The effect of the experimental conditions on the formation of these compounds was studied. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1562–1570, October, 2007.     

Synthesis from geraniol of (2<Emphasis Type="Italic">E</Emphasis>,6<Emphasis Type="Italic">E</Emphasis>,10<Emphasis Type="Italic">E</Emphasis>,14<Emphasis Type="Italic">E</Emphasis>)-16-hydroxygeranylgeraniol and some of its derivatives

Several α,ω-bifunctional derivatives of E,E,E-geranylgeraniol were prepared via convergent synthesis starting with geraniol (8), which was converted in three steps into the tetrahydropyranyl ether of 8-chlorogeraniol (9) and 8-hydroxygeranylphenylsulfone (10). Combination of synthons 9 and 10 with subsequent reductive removal of the phenylsulfonyl group produced the tetrahydropyranyl ether of ω-hydroxygeranylgeraniol (5), hydrolysis of which gave exclusively trans-ω-hydroxygeranylgeraniol (1). Derivatives 5–7 of geranylgeraniol were synthesized using standard methods. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 3, pp. 231–234, May–June, 2007.     

3,3,3-Trifluoro-<Emphasis Type="Italic">N</Emphasis>′-(3-trifluoromethylphenyl)-1,2-propanediamine and its <Emphasis Type="Italic">N</Emphasis>-mono-and <Emphasis Type="Italic">N,N</Emphasis>-dicarboxyethyl derivatives: synthesis,protolytic and complexation properties

3,3,3-Trifluoro-N′-(3-trifluoromethylphenyl)-1,2-propanediamine (5) was synthesized by the reaction of 2-diazo-1,1,1-trifluoro-3-nitropropane or 3,3,3-trifluoro-1-nitropropene with 3-aminobenzotrifluoride followed by the reduction of the nitro group. The Michael 1,4-addition of diamine 5 to acrylic acid occurs only at the N(1) atom and affords N-mono-or N,N-dicarboxyethyl derivatives 6 and 7, depending on the reactant ratio. Protolytic equilibria 5–7 in aqueous solutions were studied by pH-potentiometry and UV spectroscopy. Only the aliphatic amino group can be protonated in an aqueous solution, while the aromatic amino group remains unprotonated even in 12 M HCl. The stability constants of transition metal (Cu²⁺, Ni²⁺, Zn²⁺) complexes with ligands 5–7 were determined by pH-potentiometric titration. The stability of the complexes and selectivity of the ligands toward Cu²⁺ ions increase with an increase in the number of N-carboxyethyl groups. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2465–2469, November, 2005.     

4-Hydroxy-2-quinolones 126. 1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-<Emphasis Type="Italic">ij</Emphasis>]quinoline-2-carboxylic acid hydrazide and its derivatives

A preparative method has been developed for the synthesis of 1-hydroxy-3-oxo-5,6-dihydro-3H pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hydrazide and its derivatives. The results of a study of the antitubercular activity of the synthesized compounds are presented. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1196–1203, August, 2007.     

Synthesis of esters of <Emphasis Type="Italic">m</Emphasis>-C(7)-<Emphasis Type="Italic">iso</Emphasis>-propylcarboran-C(1)-carboxylic acid,natural terpene alcohols,and plant phenols

Previously undescribed esters 1b-21b were prepared by reaction of cetyl alcohol 1a, terpene alcohols 2a-16a, plant phenols 17a-19a, and alcohols 20a and 21a with m-C(7)-iso-propylcarboran-C(1)-carboxylic acid.Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 388–392, September–October, 2004.     

Carboxylic Acids from <Emphasis Type="Italic">Phyllanthus urinaria</Emphasis>

Five compounds, terephthalic acid mono-[2-(4-carboxy-phenoxycarbonyl)-vinyl] ester (1), (E)-3-(5′-hydroperoxy-2,2′-dihydroxy[1,1′-biphenyl]-4-yl)-2-propenoic acid (2), 3,4,5-trihydroxybenzoic acid (3), succinic acid (or butanedioic acid) (4), and 2,3,4,5,6-pentahydroxybenzoic acid (5), were isolated from Phyllanthus urinaria. The structures of these compounds were elucidated by means of spectral techniques including IR, MS, and 1D/2D NMR. 1 and 2 are new compounds.__________Published in Khimiya Prirodnykh Soedinenii, No. 1, pp. 14–17, January–February, 2005.     

Synthesis of new 1<Emphasis Type="Italic">H</Emphasis>-pyridazine derivatives <Emphasis Type="Italic">peri</Emphasis>-annelated with acenaphthene and acenaphthylene

The reaction of 6-acetyl-5-hydroxyacenaphthene with methylhydrazine afforded 1,3-dimethyl-1H-6,7-dihydroacenaphtho[5,6-de]pyridazine. Its dehydrogenation with chloranil gave 1,3-dimethyl-1H-acenaphtho[5,6-de]pyridazine, which is a heteroaromatic compound with an essentially new topology of the ρsystem. The reaction of 3-methyl-1H-6,7-dihydroacenaphtho[5,6-de]pyridazine with 3,5-di-tert-butyl-1,2-benzoquinone yielded a dimer containing the acenaphthene and acenaphthylene moieties of peri-annelated 1H-1,2-diazines connected in positions 1′ and 9.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 777–780, March, 2005.     

Poly[3-(3,4-dihydroxyphenyl)glyceric acid] from Stems of <Emphasis Type="Italic">Symphytum asperum</Emphasis> and <Emphasis Type="Italic">S. caucasicum</Emphasis>

Two high-molecular-weight (>1000 kDa) water-soluble preparations were isolated from stems of Symphytum asperum and S. caucasicum. Their basic component was established as poly[hydroxy-1-carboxy-2-(3,4-dihydroxyphenyl)ethylene], analogous to that of high-molecular-weight (>1000 kDa) preparations from roots of these same plants, using IR and NMR spectral data. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 4, pp. 303–305, July–August, 2005. An erratum to this article is available at .     

4-Hydroxy-2-quinolones. 122. 1-Hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-<Emphasis Type="Italic">ij</Emphasis>]-quinoline-2-carboxylic acid hetarylamides as potential antitubercular agents

An improved method is reported for the synthesis of a series of 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]quinoline-2-carboxylic acid hetarylamides. The antitubercular activity of all of the compounds prepared has been studied. The structure-biological activity dependence revealed is discussed. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1023–1033, July, 2007.     

Synthesis and biological activity of <Emphasis Type="Italic">N</Emphasis>-(2-hydroxyethyl)cytisine derivatives

Derivatives of N-(2-hydroxyethyl)cytisine, N-(2-hydroxypropyl)-, N-(2-hydroxy-2-(1-adamantyl)ethyl)-, and N-(2-hydroxy-2-phenylethyl)cytisine, were synthesized by reduction of N-(2-oxopropyl)-, N-(2-oxo-2-(1-adamantyl)ethyl)-and N-(2-oxo-2-phenylethyl)cytisine with metal hydrides. The antiarrhythmic and analgesic activities of the prepared compounds were investigated. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 2, pp. 157–162, March–April, 2007.     

4-Hydroxy-2-quinolones 121. Synthesis and biological properties of 1-hydroxy-3-oxo-5,6-dihydro-3h-pyrrolo[3,2,1-<Emphasis Type="Italic">ij</Emphasis>]quino-line-2-carboxylic acid alkylamides

A simple method is proposed for preparing 1-hydroxy-3-oxo-5,6-dihydro-3H-pyrrolo[3,2,1-ij]-quinoline-2-carboxylic acid alkylamides. For the case of the secondary butylamide features of the steric structure of the synthesized compounds is discussed. The results of a study of their anti-inflammatory and diuretic activities are presented. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1015–1022, July, 2007.     

Structural analysis of <Emphasis Type="Italic">w</Emphasis>/<Emphasis Type="Italic">o</Emphasis>/<Emphasis Type="Italic">w</Emphasis> multiple emulsions by means of DSC

Summary The properties of the inner and the external aqueous phases, were studied in w/o/w multiple emulsions with light microscopic image analysis and differential scanning calorimetry (DSC). The importance of multiple emulsions lies in the presence of these aqueous phases, making them available for sustained, controlled drug delivery systems. Differentiation of these two aqueous phases, studying the effect of manufacturing technology on droplet structure, quantitative determination of phase volumes and any changes occurring during storage are essential when planning w/o/w emulsions. The present study uses microscopic observations combined with DSC measurements in order to identify the formed structure, at developmental stage in case of different components, preparation methods, and stirring rates. These tools are beneficial during manufacturing as in process controls, or to ensure product quality.     

Chemical properties of <Emphasis Type="Italic">N</Emphasis>-polyfluoroethylimidazole and -pyrrole derivatives

Bromination, acylation, nitration, and metallation of imidazole and pyrrole derivatives containing the difluoromethylene fragment at the N atom were studied. 1-(1,1,2,2-Tetrafluoroethyl)pyrrole, 1-(1,1,2,2-tetrafluoroethyl)imidazole, and 1-(2-chloro-1,1,2-trifluoroethyl)imidazole were used as substrates. 1-Alkyl-3-(1,1,2,2-tetrafluoroethyl)- and 1-alkyl-3-(2-chloro-1,1,2-trifluoroethyl)imidazolium iodides were obtained. These can be used as intermediates for preparation of new ionic liquids of the imidazole series and 1-alkyl-3-polyfluoroethylimidazole-2-thiones.__________Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 781–787, March, 2005.     

Reaction of 2-methoxy-1,3,2-dioxaphosphorino[4,5-<Emphasis Type="Italic">b</Emphasis>]pyridin-4(4<Emphasis Type="Italic">H</Emphasis>)-one with hexafluoroacetone

The reaction of the di-O-trimethylsilyl derivative of 2-hydroxynicotinic acid with methyl phosphodichloridite afforded 2-methoxy-1,3,2-dioxaphosphorino[4,5-b]pyridin-4(4H )-one. The NMR spectrkscopic data suggest that the reaction of the latter with hexafluoroacetone produces unstable 2-methoxy-2,5-dioxo-4,4-bis(trifluoromethyl)-4,5-dihydro-1,3,2-dioxaphosphepino[4,5-b]pyridine, which is readily transformed into 9-methyl-2,5-dioxo-4,4- bis(trifluoromethyl)-4,5-dihydro-1,3,2-dioxaphosphepino[4,5-b]pyrid-9-inium-2-oate. The structure of the hydrolysis product of the latter, viz., 1-methyl-3-(2-hydroxy-3,3,3-trifluoro-2- trifluoromethylpropanoyl)pyridin-2-one, was established by X-ray diffraction analysis.Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1640–1646, August, 2004.     

A one-pot synthesis of 8-amino-1-methoxy-6<Emphasis Type="Italic">H</Emphasis>-dibenzo[<Emphasis Type="Italic">b,d</Emphasis>]pyran-6-one

8-Amino-1-methoxy-6H-dibenzo[b,d]pyran-6-one was synthesized in a one-pot reaction of 2′,6′-dimethoxy-4-nitro-1,1′-biphenyl-2-carboxylic acid methyl ester using hydroiodic acid as a reagent to effect O-demethylation, lactonization, and nitro reduction to amine. This new reaction represents an improved alternative to the previously reported three-step reactions for this transformation.