S. I. Kovalenko

[1,2,4]Triazino[2,3- с ]quinazolines 2*. Synthesis, structure, and anticonvulsant activity of new 3′-R 1 -spiro[(aza/oxa/thia)cycloalkyl-1(3, 4),6′-[1,2,4]triazino[2,3- c ]quinazolin]-2′(7′ H )-ones

Previously unknown 3′-R1-spiro[(aza/oxa/thia)cycloalkyl-1(3, 4),6′-[1,2,4]triazino[2,3-c]quinazolin]-2′(7′H)-ones were obtained on the basis of (5+1) cyclocondensation reaction of substituted 6-R1-3-(2-aminophenyl)-1,2,4-triazin-5(2Н)-ones with cyclic ketones. It was established that the steric and electronic factors of cyclic ketones did not affect the reaction duration and product yields. The structure of the synthesized compounds was proved by 1Н and 13C NMR spectroscopy, mass spectrometry, and X-ray structural analysis. The synthesized compounds were characterized as promising anticonvulsants.

[1,2,4]Triazino[2,3-с]quinazolines 3*. Structure and anticancer activity of products obtained from reaction of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with aryl iso(thio)cyanates

Reactions of 3-(2-aminophenyl)-6-R-1,2,4-triazin-5(2H)-ones with aryl isocyanates and aryl isothiocyanates were studied by using solvents of various nature, as well as varying the temperature regime and process duration. The series of synthesized compounds was shown to exhibit pronounced cytostatic activity with respect to specific cell lines of melanoma, non-small cell lung cancer, kidney cancer, and cancer of central nervous system.

Спектрофотометрическое определение оригинальной субстанции Хинабут и таблетированной лекарственной формы на её основе

Aim. The sensitive, efficient and express method for original active pharmaceutical ingredient Quinabut determination and based on it tablets was described in presented article. Methods and results. Detailed analysis of physicochemical properties of studied compound conducted by authors allowed to substantiate the usage of purified water as solvent. It was shown, that UV-spectra of active pharmaceutical ingredient was characterized by absorption maximum at 232 nm. Length wavexa0 mentioned above was used for further studies. The elaborated method is based on evaluation of proper absorption of active pharmaceutical ingredient solution, data of absorption of studied sample and standard solution was used for calculation of the final results. Conclusions. Correctness and suitableness of proposed method for realization of planned tasks were proven by conduction of standardized validation procedure. The evaluation of linearity was conducted in range of concentration wherein the compliance with Beer law was observed. Indexes of linear dependence, that were obtained according to SPhU recommendations (correlation coefficient r, residual sum of deviation squares, free term of linear regression) were in compliance with requirements for linear dependence parameters. Conducted evaluation of precision and accuracy of method showed it compliance with requirements of SPhU. The prediction of total irreproducibility was conducted for confirmation of method correctness by repeating in other laboratories. It was shown that proposed method would produce correct results in other laboratories.

Synthesis, anticancer and FGFR1 inhibitory activity of isoindolo[2,1-a][1,2,4]triazino[2,3-c]quinazoline derivatives

Presented manuscript describes the synthesis, antitumor and FGFR1 inhibitory activity of novel isoindolo[2,1-a] [1,2,4]triazino[2,3-c]quinazolines. It was shown that mentioned above substances may be prepared by interaction of 3-(2-amino-3-R2-5-R3-phenyl)-6-R1-1,2,4-triazin-5(2H)-ones with 2-formylbenzoic and 6-formyl-2,3-dimethoxybenzoic (opianic) acids in acetic acid. It was shown that proper 2-(2-oxo-3-R-6,7-dihydro-2H-[1,2,4]triazino[2,3-c]quinazolin- 6-yl)benzoic acids (or corresponded dimethoxysubstituted analogues) may be considered as intermediates of the reaction. Spectral properties of synthesized compounds were studied, it was shown that protons in position 8 were observed at low field as result of the presence of hydrogen bond between hydrogen at position 8 and oxygen at position 10. The anticancer assay data allowed to identify synthesized compounds as promising antitumor agents. The FGFR1 inhibitory activity of synthesized compounds was detected and docking study aimed to the evaluation of mentioned action was conducted.

Методология поиска противоопухолевого действия (2-оксо-2H-[1,2,4]-триазино[2,3-с]хиназолин-6-ил)тионов с помощью QSAR и докинговых исследований

No1 (88) 2015 ISSN 2306-4145 I is well known, that derivatives of quinazoline have signifi cant anticancer potential, that has been proved by our previous articles [2,10,11], and also by many other researchers. What is even more persuasive, that based on quinazoline skeleton a set of anticancer drugs is being used as an inhibitor of the tyrosine kinase activity associated with EGFR (epidermal growth factor receptor), HER2/neu (Human EGFR type 2), vascular endothelial growth factor receptor (VEGFR) and the RET-tyrosine kinase, (Erlotinib, Lapatinib, Vandetanib) [1,4–6]. In most cases such drugs are prescribed to treat Non-small lung cancer, generally in combination with other drugs (Capecitabine, Letrozole, Gemcitabine, others). Such, without any doubt focused search of a new active anticancer compound, among quinazoline derivatives is a cutting-edge theme. So the aim of our work was to reveal the probable mechanism of action based on QSAR-analysis, docking and interaction with available protein kinase, namely CK2 [18]. To fi nd out reliable QSAR-model is the task, solving with, would help a lot for future work not only for our research group, but for many others too. Materials and methods Anticancer activity. The library of compounds, that consists of 76 derivatives of (2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl)thiones was obtained, as a part of PhD research. A range of (2-oxo-2H-[1,2,4]triazino[2,3-c]quinazolin-6-yl) thiones is a promising object for a search of effective anticancer compounds. Cooperating with international research program (Development Therapeutic Program, DTP) of National Cancer Institute (NCI) these derivatives were preliminary tested in vitro for 60 cancer cell lines at a concentration of 10-5 M [3]. Some of them were investigated for dose dependent action in 5 concentrations (10-4-10-8 M). But the amount of those compounds is not enough to built QSAR-model. Detailed description of the procedure is written in http://dtp.nci.nih.gov/. So data of UDC 547.873’856.1:615.277.3]-047.72:167З метою розробки нової групи інгібіторів протеїнкіназ виконали рецептор-орієнтований віртуальний скринінг (докінг, QSAR-моделювання) та біохімічне тестування ряду похідних (2-оксо-2H-[1,2,4]триазино[2,3-с]хіназолін-6-іл)тіону. Встановили, що ці сполуки являють собою перспективні об’єкти для розробки активних і селективних інгібіторів протеїн СК2 кінази. Здійснене дослідження дало можливість зробити значний внесок у пошук нових ефективних протипухлинних сполук в ряду (2-оксо-2H-[1,2,4]триазино[2,3-с]хіназолін-6-іл)тіонів та може бути використане як теоретичне підґрунтя для структурної оптимізації, спрямованої на створення нових лікарських засобів.