Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic agents had prospects for reducing toxic side effects of chemotherapy in vivo, which would be carried out only after the preclinical studies.

No abstract

No abstract

Methyl 5-hydroxy-4-oxo-4H-pyran-2-carboxylate was synthesized by esterification of methanol with comenic acid under acidic catalysis. The obtained ester was alkylated with 3-(chloromethyl)-5-phenylisoxazole and 4,5-dichloro-3-(chloromethyl)isothiazole to afford corresponding conjugates containing isoxazole and isothiazole moieties which then were transformed into water-soluble Li-salts. During the bioassays of synthesized isoxazole and isothiazole derivatives of comenic acid in mixtures with first-line antitumor drug Temobel (Temozolomid) used in brain tumors chemotherapy, a synergetic effect was observed.

No abstract

No abstract

By a series of successive transformations, 5-arylisoxazole-3-carboxylic acids (aryl = phenyl, p-tolyl, 2,5-dimethylphenyl) have been converted into 5-arylisoxazole-3-hydroxamic acids, which undergo rearrangement by the action of aqueous KOH to form 3,4-substituted 1,2,5-oxadiazoles. The structure of one of them, 1-(2,5-dimethylphenyl)-2-(4-hydroxy-1,2,5-oxadiazol-3-yl)ethanone, has been confirmed by single crystal X-ray analysis.The chemistry of 1,2,5-oxadiazole (trivial name furazan) is of great interest, because a large number of compounds incorporating furazan cycle possess a wide spectrum of biological activity. 1 Moreover, they attract great attention as energetic materials, 2 dyes, and precursors for organic synthesis of useful products. 3 There are different methods available for the synthesis of furazans. One of them is based on the mononuclear heterocyclic rearrangement of the isoxazoles bearing an oxime group in the 3 position of the heterocycle. 4 Hydroxamic acids can be considered as synthetic equivalents of oximes as they can exist in two tautomeric forms, keto or enol (Scheme 1). 5 The latter is produced in low percentage, is less stable, and contains the oxime moiety. Scheme 1 Tautomeric forms of hydoxamic acidsThe transformation of isoxazolylhydroxamic acids and their derivatives into furazans is not described up till now. We intended to synthesize the 5-arylisoxazole-3-hydroxamic acids (aryl = Ph, 3-MeC 6 H 4 , 2,5-Me 2 C 6 H 3 ) 1-3 and their O-acetyl derivatives 4-6, and to study the possibility of their use in obtaining substituted 1,2,5-oxadiazoles via mononuclear heterocyclic rearrangement. The 5-arylisoxazole-3-carboxylic acids 7-9 were taken as starting compounds. Recently, we have reported their synthesis from the corresponding available 5-arylisoxazole-3-carbaldehyde oximes. 6 Two approaches were tested for the synthesis of arylisoxazole-3-hydroxamic acids 1-3. One of them included the amidation of methyl 5-arylisoxazole-3-carboxylates 10-12 by reaction with hydroxylamine. Another path consisted in acylation of hydroxylamine by the action of 5-arylisoxazole-3-carbonyl chlorides 13-15, easily obtained by the reaction of acids 7-9 with thionyl chloride. The former approach was found to be more preferable, as it allows to obtain the target hydroxamic acids 1-3 in higher yields (75-88% instead of 51-60% in the latter approach) and with higher purity. Thus, the first approach was used in practice. Acetylation of hydroxamic acids proceeded selectively on the hydroxy group and led to the corresponding acetyl derivatives 4-6 in 83-96% yields (Scheme 2).At first it was planned to convert the O-acetylhydroxamic acids 4-6 into 3-amino-5-arylisoxazoles by heating with aqueous alkali. The conversion of O-acylhydroxamic acids to isocyanates and further to amines or ureas is well known as Lossen rearrangement. 7 However, the process proceeded quite differently and led to 1-aryl-2-(4-hydroxy-1,2,5-oxadiazol-3-yl)ethanones 16-18, that is, substituted furazans (Scheme 2). The hydrolysis of acylated fragme...

We report for the first time cyclic phosphine-free “head to tail” N,N,N pincer-like (pincer complexes mimicking) N-(pyrimidin-2-yl)-1,2-azole-3-carboxamide Pd­(II) complexes with deprotonated amide groups as high-turnover catalysts (TON up to 106, TOF up to 1.2 × 107 h–1) for cross-coupling reactions on the background of up to quantitative yields under Green Chemistry conditions. The potency of the described catalyst family representatives was demonstrated in Suzuki–Miyaura, Mizoroki–Heck, and Sonogashira reactions on industrially practical examples. Corresponding ligands could be synthesized based on readily available reagents through simple chemical transformations. Within the complex structures, a highly unusual 1,3,5,7-tetraza-2,6-dipalladocane frame could be observed.