Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines

Aim. To synthesize a series of novel 3H-thiazolo[4,5-b]pyridine-2-ones by structural modification of the core heterocycle in its N3- and N6-positions and to evaluate their anticancer activity in vitro on several tumor cell lines. Methods. Organic synthesis, 1 H-NMR spectroscopy, trypan blue cell v...

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Дата:	2012
Автори:	Chaban, T.I., Panchuk, R.R., Klenina, O.V., Skorokhyd, N.R., Ogurtsov, V.V., Chaban, I.G.
Формат:	Стаття
Мова:	English
Опубліковано:	Інститут молекулярної біології і генетики НАН України 2012
Назва видання:	Вiopolymers and Cell
Теми:	Bioorganic Chemistry
Онлайн доступ:	https://nasplib.isofts.kiev.ua/handle/123456789/156904
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Цитувати:	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines / T.I. Chaban, R.R. Panchuk, O.V. Klenina, N.R. Skorokhyd, V.V. Ogurtsov, I.G. Chaban // Вiopolymers and Cell. — 2012. — Т. 28, № 5. — С. 389-396. — Бібліогр.: 18 назв. — англ.

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spelling	nasplib_isofts_kiev_ua-123456789-1569042025-02-09T10:41:59Z Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines Синтез та вивчення протипухлинної активності деяких тіазоло[4,5-b] піридинів Синтез и изучение противоопухолевой активности некоторых тиазоло[4,5-b]пиридинов Chaban, T.I. Panchuk, R.R. Klenina, O.V. Skorokhyd, N.R. Ogurtsov, V.V. Chaban, I.G. Bioorganic Chemistry Aim. To synthesize a series of novel 3H-thiazolo[4,5-b]pyridine-2-ones by structural modification of the core heterocycle in its N3- and N6-positions and to evaluate their anticancer activity in vitro on several tumor cell lines. Methods. Organic synthesis, 1 H-NMR spectroscopy, trypan blue cell viability assay. Results. A new convenient synthetic approach was developed and optimized conditions were studied for the reaction of preparation of 3Hthiazolo[4,5-b]pyridin-2-one derivatives. 5,7-Dimethyl-3H-thiazolo[4,5-b]pyridin-2-one and 6-phenylazo-5,7- dimethyl-3H-thiazolo[4,5-b]pyridin-2-one were obtained by [3 + 3]cyclocondensation of 4-iminothiazolidone2 with acetylacetone and -phenylazoacetylacetone in methanol medium in the presence of sodium methylate. They were used as starting compounds for further structural modification of the core thiazolo[4,5-b]pyridine heterocycle in its 3- and 6-positions. On the basis of in vitro cytotoxicity studies of synthesized compounds several structure-functional relationships underlying anticancer potential of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin2-one derivatives were identified. Conclusions. 3H-thiazolo[4,5-b]pyridin-2-one can be considered as a promising molecular scaffold for rational design of potential anticancer drug candidates. Introduction of phenylazo substitute at C6-position of 3H-thiazolo[4,5-b]pyridin-2-one proved to be the most efficient, as it led to 3-fold increase of its anticancer potential. Keywords: thiazolo[4,5-b]pyridines, [3+ 3]cyclocondensation, structural modification, antitumor activity Мета. Синтезувати серію нових похідних 3H-тіазоло[4,5-b]піридин-2-ону, модифікуючи структуру базового гетероциклу за 3-м і 6-м положеннями. Дослідити протипухлинну активність одержаних сполук in vitro на деяких лініях злоякісних клітин ссавців. Методи. Органічний синтез, ПМР-спектроскопія, визначення життєздатності клітин за їхнім забарвленням трипановим синім. Результати. Запропоновано зручний синтетичний підхід і знайдено оптимальні умови для проведення реакцій отримання 3H-тіазоло[4,5-b]піридин-2-онів. Реакцією [3 + 3] циклоконденсації 4-іміно-2-тіазолідону з ацетилацетоном і фенілазоацетилацетоном у середовищі метанолу за присутності метилату натрію одержано 5,7-диметил-3H-тіазоло[4,5-b]піридин-2-он і 6-фенілазо-5,7-диметил-3H-тіазоло[4,5-b]піридин-2-он, які використано як вихідні речовини для майбутньої структурної модифікації базового тіазоло[4,5-b]піридинового гетероциклу за 3-м і 6-м положеннями. Введенням вихідних сполук у реакції ціаноетилювання з подальшим гідролізом отриманого продукту алкілування, яке відбувається через стадію одержання відповідних калійних солей, з наступним гідразинолізом продуктів, а також у реакцію відновлювального розщеплення з дальшим ацилюванням продуктів одержано серію нових похідних 3H-тіазоло[4,5-b]піридин-2-ону. Висновки. Тіазоло[4,5-b]піридин-2-он можна вважати перспективним молекулярним каркасом, що дозволяє застосовувати зазначену конденсовану систему для раціонального дизайну потенційних лікарських засобів з широким спектром різних видів біологічної активності. Найефективнішим виявилося введення в 6-те положення тіазоло[4,5-b]піридин-2-ону фенілазо замісника, що дало можливість утричі підвищити його протипухлинний потенціал. Ключові слова: тіазоло[4,5-b]піридини, [3+3] циклоконденсація, структурна модифікація, протипухлинна активність. Цель. Синтезировать серию новых производных 3H-тиазоло[4,5- b]пиридин-2-она, модифицируя структуру базового гетероцикла в 3-м и 6-м положениях. Исследовать противоопухолевую активность полученных соединений in vitro на некоторых линиях злокачестенных клеток млекопитающих. Методы. Органический синтез, ПМР-спектроскопия, определение жизнеспособности клеток окрашиванием трипановым синим. Результаты. Предложен удобный синтетический подход и установлены оптимальные условия для проведения реакций получения 3H-тиазоло[4,5-b]пиридин-2-онов. Реакцией [3+3] циклоконденсации 4-имино-2-тиазолидона с ацетилацетоном и фенилазоацетилацетоном в среде метанола в присутствии метилата натрия получены 5,7-диметил-3H-тиазоло[4,5-b]пиридин-2-он и 6-фенилазо-5,7-диметил- 3H-тиазоло[4,5-b] пиридин-2-он, которые использованы как исходные вещества для будущей структурной модификации базового тиазоло[4,5-b]пиридинового гетероцикла в 3-м и 6-м положениях. Введением исходных соединений в реакции цианоэтилирования с последующим гидролизом полученного продукта алкилирования, проходящего через стадию выделения соответствующих калийных солей, с дальнейшим гидразинолизом продуктов, а также в реакцию восстановительного расщепления со следующим ацилированием продуктов получена серия новых производных 3H-тиазоло[4,5-b]пиридин-2-она. Выводы. Тиазоло[4,5-b]пиридин- 2-он можна считать перспективным молекулярным каркасом, позволяющим использовать указанную конденсированную систему для рационального дизайна потенциальных лекарственных средств с широким спектром разных видов биологической активности. Наиболее эффективним оказалось введение в 6-е положение тиазоло[4,5-b]пиридин-2-она фенилазо заместителя, что дало возможность втрое повысить его противоопухолевый потенциал. Ключевые слова: тиазоло[4,5-b]пиридины, [3 + 3] циклоконденсация, структурная модификация, противоопухолевая активность. 2012 Article Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines / T.I. Chaban, R.R. Panchuk, O.V. Klenina, N.R. Skorokhyd, V.V. Ogurtsov, I.G. Chaban // Вiopolymers and Cell. — 2012. — Т. 28, № 5. — С. 389-396. — Бібліогр.: 18 назв. — англ. 0233-7657 DOI: http://dx.doi.org/10.7124/bc.000075 https://nasplib.isofts.kiev.ua/handle/123456789/156904 547.789.69 + 615.277.3 en Вiopolymers and Cell application/pdf Інститут молекулярної біології і генетики НАН України
institution	Digital Library of Periodicals of National Academy of Sciences of Ukraine
collection	DSpace DC
language	English
topic	Bioorganic Chemistry Bioorganic Chemistry
spellingShingle	Bioorganic Chemistry Bioorganic Chemistry Chaban, T.I. Panchuk, R.R. Klenina, O.V. Skorokhyd, N.R. Ogurtsov, V.V. Chaban, I.G. Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines Вiopolymers and Cell
description	Aim. To synthesize a series of novel 3H-thiazolo[4,5-b]pyridine-2-ones by structural modification of the core heterocycle in its N3- and N6-positions and to evaluate their anticancer activity in vitro on several tumor cell lines. Methods. Organic synthesis, 1 H-NMR spectroscopy, trypan blue cell viability assay. Results. A new convenient synthetic approach was developed and optimized conditions were studied for the reaction of preparation of 3Hthiazolo[4,5-b]pyridin-2-one derivatives. 5,7-Dimethyl-3H-thiazolo[4,5-b]pyridin-2-one and 6-phenylazo-5,7- dimethyl-3H-thiazolo[4,5-b]pyridin-2-one were obtained by [3 + 3]cyclocondensation of 4-iminothiazolidone2 with acetylacetone and -phenylazoacetylacetone in methanol medium in the presence of sodium methylate. They were used as starting compounds for further structural modification of the core thiazolo[4,5-b]pyridine heterocycle in its 3- and 6-positions. On the basis of in vitro cytotoxicity studies of synthesized compounds several structure-functional relationships underlying anticancer potential of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin2-one derivatives were identified. Conclusions. 3H-thiazolo[4,5-b]pyridin-2-one can be considered as a promising molecular scaffold for rational design of potential anticancer drug candidates. Introduction of phenylazo substitute at C6-position of 3H-thiazolo[4,5-b]pyridin-2-one proved to be the most efficient, as it led to 3-fold increase of its anticancer potential. Keywords: thiazolo[4,5-b]pyridines, [3+ 3]cyclocondensation, structural modification, antitumor activity
format	Article
author	Chaban, T.I. Panchuk, R.R. Klenina, O.V. Skorokhyd, N.R. Ogurtsov, V.V. Chaban, I.G.
author_facet	Chaban, T.I. Panchuk, R.R. Klenina, O.V. Skorokhyd, N.R. Ogurtsov, V.V. Chaban, I.G.
author_sort	Chaban, T.I.
title	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines
title_short	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines
title_full	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines
title_fullStr	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines
title_full_unstemmed	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines
title_sort	synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines
publisher	Інститут молекулярної біології і генетики НАН України
publishDate	2012
topic_facet	Bioorganic Chemistry
url	https://nasplib.isofts.kiev.ua/handle/123456789/156904
citation_txt	Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines / T.I. Chaban, R.R. Panchuk, O.V. Klenina, N.R. Skorokhyd, V.V. Ogurtsov, I.G. Chaban // Вiopolymers and Cell. — 2012. — Т. 28, № 5. — С. 389-396. — Бібліогр.: 18 назв. — англ.
series	Вiopolymers and Cell
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fulltext	389 BIOORGANIC CHEMISTRY UDC 547.789.69 + 615.277.3 Synthesis and evaluation of antitumor activity of some thiazolo[4,5-b]pyridines T. I. Chaban, R. R. Panchuk1, O. V. Klenina, N. R. Skorokhyd1, V. V. Ogurtsov, I. G. Chaban Danylo Halytsky Lviv National Medical University 69, Pekarska Str., Lviv, Ukraine, 79010 1Institute of Cell Biology, NAS of Ukraine 14/16, Drahomanov Str., Lviv, Ukraine, 79005 chabantaras@ukr.net; rpanchuk@ukr.net Aim. To synthesize a series of novel 3H-thiazolo[4,5-b]pyridine-2-ones by structural modification of the core he- terocycle in its N3- and N6-positions and to evaluate their anticancer activity in vitro on several tumor cell lines. Methods. Organic synthesis, 1 H-NMR spectroscopy, trypan blue cell viability assay. Results. A new convenient synthetic approach was developed and optimized conditions were studied for the reaction of preparation of 3H- thiazolo[4,5-b]pyridin-2-one derivatives. 5,7-Dimethyl-3H-thiazolo[4,5-b]pyridin-2-one and 6-phenylazo-5,7- dimethyl-3H-thiazolo[4,5-b]pyridin-2-one were obtained by [3 + 3]cyclocondensation of 4-iminothiazolidone- 2 with acetylacetone and �-phenylazoacetylacetone in methanol medium in the presence of sodium methylate. They were used as starting compounds for further structural modification of the core thiazolo[4,5-b]pyridine he- terocycle in its 3- and 6-positions. On the basis of in vitro cytotoxicity studies of synthesized compounds several structure-functional relationships underlying anticancer potential of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin- 2-one derivatives were identified. Conclusions. 3H-thiazolo[4,5-b]pyridin-2-one can be considered as a promi- sing molecular scaffold for rational design of potential anticancer drug candidates. Introduction of phenylazo substitute at C6-position of 3H-thiazolo[4,5-b]pyridin-2-one proved to be the most efficient, as it led to 3-fold in- crease of its anticancer potential. Keywords: thiazolo[4,5-b]pyridines, [3+ 3]cyclocondensation, structural modification, antitumor activity. Introduction. The development of diverse strategies for the directed synthesis of potential drug candidates consists of several steps, starting from scaffold hop- ping towards the hit compounds identification and their further in silico rational design. Molecular scaffold-ba- sed design of 4-thiazolidine analogs is inspired by both the variety of their pharmacological actions and accessi- bility of chemical modification of their structure. A se- ries of 4-thiazolidines are at different stages of clinical trials as anti-inflammatory, antitumor, antimicrobial, antiviral, cardiovascular and thrombolytic drug candi- dates [1]. The thiazolidine based heterocycles and their ana- logs fused w³th the pyridine ring serve as attractive tar- gets for developing efficient protocols to prepare thia- zolo[4,5-b]pyridine scaffolds the biological activity of which still remains poorly studied. There is little information available about the biolo- gical activity of thiazolo[4,5-b] pyridines. For examp- le, some of their derivatives were described as useful antimicrobial agents effective against a variety of human and veterinary pathogens including Gram-positive and Gram-negative aerobic and anaerobic bacteria, as well as mycobacteria [2]. Thiazolo[4,5-b]pyridines also show potent inhibitory activities for A�42 fibrillization at a micromolar level for Alzheimer’s disease treatment [3], some of them are H3 receptor antagonists [4], others were revealed to activate the GK enzyme in vitro and significantly reduce glucose levels [5]. Some thiazolo [4,5-b]pyridine analogues are potent antistaphylococ- ISSN 0233–7657. Biopolymers and Cell. 2012. Vol. 28. N 5. P. 389–396 � Institute of Molecular Biology and Genetics, NAS of Ukraine, 2012 390 CHABAN T. I. ET AL. cal compounds with suboptimal drug-like properties [6]. They act as inhibitors of the bacterial cell-division protein, FtsZ. Several compounds among these substan- ces were found to possess fungicidal action [7] or act as antagonists of metabotropic glutamate receptors 5 (mGluR5) [8], as well as epidermal growth factor re- ceptors [9] and a number of other enzymes [10, 11]. However, the information on antitumor activity of the mentioned bicycle derivatives of 4-thiazolidones is still missing. Up to now just a few compounds of such chemical structure have been tested against some hu- man tumor cell lines in vitro [1, 12]. Several studies point out that 4-thiazolidone based bicyclic analogues, in particular pyrazole and isoxazole derivatives, can act as inhibitors of HSP90, an ATP-dependent molecular chaperon [12]. In normal cells HSP90 is involved in protein folding, but in cancer cells it can stabilize oncoproteins v-Src, Bcr/Abl and mutant products of p53 gene, thus pos- sessing strong anti-apoptotic activity [13]. Several HSP90 inhibitors, such as geldanamycin, have already shown some promising effects in clinical trials [14], but search for other small molecule inhibitors of HSP90 still remains an active area of cancer research. Tyrosine Kinases (TK) are other possible antican- cer targets for 4-thiazolidone derivatives. TK play a cru- cial role in the action of epidermal growth factor re- ceptor (EGFR), and mutation of the ATP-binding site of EGFR is closely associated with TK activity, being one of the main reasons of cell malignization by dis- rupting the formation of tumorigenic signals. That’s why the development of TK inhibitors is suggested as one of the most perspective strategies for cancer treat- ment, and some of them, such as trastuzumab (Hercep- tin®), gefitinib, imatinib have been already widely used in cancer treatment. Several five-membered hetero- cycle derivatives and fused heterocycle analogs were also found to possess the TK enzymes inhibitory activi- ty and now are at different phases of clinical trials [15]. Based on these data, the main aim of current work was the development of novel innovative approaches for organic synthesis of thiazolo[4,5-b]pyridine deriva- tives with an eye towards the discovery of isosteric fused ring compounds with the nitrogen heteroatom as a potential atom interacting with the anticancer targets mentioned above. Materials and methods. Synthetic routine for the novel compounds preparation was carried out accor- ding to common approaches used for the potential drug candidates rational design with proper «Merck» (Ger- many) chemicals implementation. The structures of all synthesized compounds were established on the basis of quantitative elemental analy- sis and spectral 1H-NMR data («Varian Mercury VX- 400», DMSO-d6 was used as a solvent, tetramethylsi- lane as a standard). Murine leukemia cells of L1210 line were obtained from the cell culture collection of R. E. Kavetsky Institu- te of Experimental Pathology, Oncology and Radiobio- logy, NAS of Ukraine, human breast adenocarcinoma cells of MDA-MD-231 lines were obtained from the cell culture collection of Ludwig Institute for Cancer Re- search (Sweden), and human melanoma cells of SK- MEL-28 line were obtained from the cell culture collec- tion of Nencki Institute of Experimental Biology PAN (Poland). Cells were cultured in DMEM medium sup- plemented with 10 % fetal calf serum («Sigma Chemi- cal Co.», USA), 50 µg/ml streptomycin («Sigma Che- mi cal Co.»), 50 units/ml penicillin («Sigma Chemical Co.») in 5 % CO2-containing humidified atmosphere at 37 oC. For experiments, cells were seeded into 24-well tis- sue culture plates («Greiner Bio-one», Germany). A cyto- toxic effect of antitumor drugs was studied under the Evo- lution 300 Trino microscope («Delta Optical», Poland) after cell staining with trypan blue dye (0.1 %) [16]. Experiments were performed in triplicate and repea- ted 3 times. Significance of the difference in a typical experiment was assessed by Student’s t-test. The level of significance was set at 0.05. Results and discussion. In our previous report we have proposed a convenient method of 5,7-dimethyl- 3H-thiazolo[4,5-b]pyridin-2-one preparation. The me- thod of thiazolo[4,5-b]pyridine scaffold construction is based on [3 + 3] cyclocondensation of 4-iminothiazoli- done-2 on account of its N,C-binucleophilic properties with dielectrophilic reagents like acetylacetone for- ming 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one (1) [17]. We discovered that a high yield of the product in the developed protocol can be achieved by keeping the reagents mixture in methanol in the presence of sodium methylate over 5 days. 391 SYNTHESIS AND EVALUATION OF ANTITUMOR ACTIVITY OF SOME THIAZOLO[4,5-b]PYRIDINES Further structural modification of thiazolo[4,5-b]py- ridine scaffold in its N3 and C6 positions was investiga- ted resulting in the preparation of its novel derivatives. The optimized conditions were used to obtain 6- phenylazo-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2- one (2) by involving �-phenylazoacetylacetone into the reaction. Taking advantage of a good hydrogen atom mobili- ty in NH group of the compound 1 N3-position allowed us to carry out its cyanoethylation which led us to de- signing 3-(5,7-dimethyl-2-oxo-thiazolo[4,5-b]pyridi- ne-3-yl)-propionitrile (3) further utilized by hydroly- sis for [the] 3-(5,7-dimethyl-2-oxo-thiazolo[4,5-b] pyri- dine-3-yl)-propionic acid (4) preparation. 3-(5,7-dimethyl-6-phenylazo-2-oxo-thiazolo[4,5-b] pyridine-3-yl)-propionitrile (5) was similarly obtained in a good yield by involving the compound 2 into cya- noethylation reaction under the same conditions as out- lined in the Fig. 1. The acidic character of the proton in the core hete- rocycle N3-position of compounds 1 and 2 promotes tendency of these compounds to transform into corres- ponding potassium salts under their treatment with po- tassium hydroxide. The obtained salts possess nucleo- philic properties and can be involved into reactions with electrophilic reagents in mild conditions. Thus the po- tassium salt of 5,7-dimethyl-3H-thiazolo[4,5-b]pyri- din-2-one and the same salt of 6-phenylazo-5,7-dime- thyl-3H-thiazolo[4,5-b]pyridin-2-one (6) were alkyla- ted with monochloracetic acid ethyl ester. The next step of our strategy was the utilization of the products in the hydrazinolysis reaction with the res- pective hydrazides preparation like 5,7-dimethyl-3H- thiazolo[4,5-b]pyridin-2-one hydrazide (7). In the sa- me way the compound 2 hydrazide is easily available while its further utilization in condensation with hetero- cyclic aldehyde reaction led us to the compound 8 for- mation. Using 3-bromopropene-1 as an alkylation agent for the compound 7 treatment allows us to get com- pound 9 (Fig. 2). The reduction decoupling reaction of 5,7-dime- thyl-6-phenylazo-3H-thiazolo[4,5-b]pyridine-2-one (2) was studied in order to obtain 6-amine-5,7-dimethyl- 3H-thiazolo[4,5-b]pyridine-2-one as a reagent for thia- zolo[4,5-b] pyridines C6-position transformations. A high yield of the targeted compound 10 was found to oc- cur in acetic acid-pyridine medium, zinc powder being used as a reduction agent. The amine group presence in its C6-position allows transforming it into appropriate 6-acetylaminoderivative (11). Dioxane was found to be the most suitable medium for the reaction of compound 10 with acetic acids chloroanhydride. The product of the compound 10 acylation with chloroacetylchloride made it possible to design 6-sulfanylacetamidederiva- tive of the core bicycle (12) by treatment it with the ap- propriate thiol (Fig. 3). We studied a cytotoxic effect of 12 synthesized com- pounds in vitro on murine leukemia cells of L1210 line, human breast adenocarcinoma cells of MDA-MD-231 line and human melanoma cells of SK-MEL-28 line S N H O NH CH 3 CH 3 O O N N H C 6 H 5 N S N H O CH 3 CH 3 N S N H O CH 3 N N C 6 H 5 CH 3 CH 2 N CH 2 N N S N O CH 3 CH 3 N N N C 6 H 5 N S N O CH 3 CH 3 N N S N O CH 3 CH 3 OH O O CH 3 CH 3 O 1 2 3 4 5 Fig. 1. Synthesis of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one (1), 6-phenylazo-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one (2), the pro- ducts of their cyanoethylation (3, 5) and hydrolysis (4) reactions (Fig. 4, a–c). For convenience these compounds were numerated as T-1–T-12. The core compound T-1 (5,7-dimethyl-3H-thiazo- lo[4,5-b]pyridin-2-one) demonstrated the weakest cyto- toxic effect on all three cell lines (growth inhibition of L1210 cells only by 25 % compared to control, MDA- MD-231 cells by 29 % and SK-MEL-28 cells only by 13 % at highest concentration 100 µM). However, the addition of phenylazo fragment to C6-position of 5,7- dimethyl-3H-thiazolo[4,5-b]pyridin-2-one molecule significantly (2–4 times) enhanced the anticancer poten- tial of core scaffold. It was revealed that resulting T-2 inhibited the growth of L1210 cell by 65 %, MDA- MD-231 cells by 82 % and SK-MEL-28 cells by 72 % at 100 µM concentration. The conjugation of beta-cya- noethyl group at N3-position of core scaffold also boos- ted its anticancer activity, but to much lower extent when compared to C6-subsituted compound T-2 (37 % growth inhibition of L1210 cells, 64 % inhibition of MDA-MD-231 and 66 % inhibition of SK-MEL-28 cells). However, the hydrolysis of compound T-3 side chain weakened its anticancer potential – we observed 18 % inhibition of L1210 cells, while for carcinoma cells no statistically significant differences between T-3 and T-4 were found – 60 % inhibition of MDA- MD-231 cells (compared to 64 % in case of T-3) and 56 % inhibition of SK-MEL-28 cells (compared to 66 % in case of T-3). Thus, the terminal cyano group at N3-position of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin- 2-one derivatives seems to play some role in their anti- leukemic activities. 392 CHABAN T. I. ET AL. N S N H O CH 3 CH 3 N S NK O CH 3 CH 3 N S N O CH 3 CH 3 O O N 2 H 4 N S N CH 3 CH 3 O O N H NH 2 N S N H O CH 3 N N C 6 H 5 CH 3 N S NK O CH 3 N N C 6 H 5 CH 3 C 3 H 5 Br N S N O CH 3 N N C 6 H 5 CH 3 N S N O CH 3 CH 3 O O N N C 6 H 5 N 2 H 4 N S N CH 3 CH 3 ON N C 6 H 5 O N N O Cl F FF N S N CH 3 CH 3 ON N C 6 H 5 O N H NH 2 1 7 2 6 8 KOH ClCH2COOC2H5 KOH ClCH2COOC2H5 9 Fig. 2. Synthesis of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one and 6-phenylazo-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one potassium salts and their structural modifications in 3-position N S N H O CH 3 N N C 6 H 5 CH 3 Zn N S N H O CH 3 NH 2 CH 3 ClCH 2 COCl N S N H O CH 3 N CH 3 O CH 3 N S N H O CH 3 N CH 3 O Cl S N S N H O CH 3 N H CH 3 O S N N S SH 2 10 12 CH3COCl 11 Fig. 3. Structural modification products of 6-phenylazo-5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one in its 6-position The conjugation of both phenylazo fragment to C6- position and beta-cyanoethyl group to N3-position of core compound T-1 did not give any cumulative effect – cytotoxic activity of T-5 on L1210 leukemia cells was practically the same as of T-3 and weaker than that of T-2 (39 % of growth inhibition at 100 µM concen- tration of T-5 compared to 37 % by T-3 and 65 % by T-2). T-5 demonstrated a bit stronger effect on carci- noma cells of MDA-MD-231 line, than on leukemia cells (66 % of growth inhibition compared to 64 % by T-3), and the same was true for SK-MEL-28 cells (70 % of growth inhibition compared to 66 % by T-3). Thus, one can see that beta-cyanoethyl group inhibits the ac- tivity of phenylazo fragment in «hybrid» molecule T-5, which suggests usage of other substitution groups at N3- position of T-1 for enhancement of its activity. Taking into consideration that T-2 possesses rela- tively high anticancer activity, but is insoluble in water, we synthesized its potassium salt. However, such pro- cedure led to almost complete loss of anticancer acti- vity of water-soluble T-6 compound (growth inhibition of L1210 cells by only 19 % at 100 µM concentration compared to 65 % inhibition by T-2, 12 % of MDA- MD-231 cells compared to 82 % by T-2). Only mela- noma cells of SK-MEL-28 line remained sensitive to T-6 (64 % growth inhibition compared to 72 % in case 393 SYNTHESIS AND EVALUATION OF ANTITUMOR ACTIVITY OF SOME THIAZOLO[4,5-b]PYRIDINES L1210, 24 h Concentration, µM MDA-MD-231, 24 h Concentration, µM SK-MEL-28, 24 h Concentration, µM 0 20 60 100 0 10 50 100R el a ti v e n u m k b e r o f a li ve c e ll s, % 0 20 60 100 0 10 50 100 0 20 60 100 0 10 50 100 0 20 60 100 0 10 50 100R el a ti ve n u m k b e r o f a li ve c e ll s, % 0 50 100 0 10 50 100 0 50 100 0 10 50 100 0 50 100 0 10 50 100 0 50 100 0 10 50 100 0 50 100 0 10 50 100 R el a ti ve n u m k b e r o f a li ve c e ll s, % 1 2 3 4 1 2 3 4 1 2 3 4 5 6 7 8 5 6 7 8 5 6 7 8 9 10 11 12 9 10 11 12 9 10 11 12 a b c Fig. 4. Comparison of cytotoxic activity of 5,7-dimethyl-3H-thiazolo [4,5-b]pyridin-2-one derivatives in murine L1210 leukemia cells (a), in human breast adenocarcinoma cells of MDA-MD-231 line (b) and human melanoma cells of SK- MEL-28 line (c) of T-2). This suggests specificity of the action of potas- sium salt of 5,7-dimethyl-6-[phenylazo]-3H-thiazolo [4,5-b]pyridin-2-one (T-6) towards melanoma cells, which can be of high importance when moving to in vi- vo studies on experimental animals. The next step of our study was further optimization of the core T-1 scaffold by obtaining hydrazide of this compound, named T-7 (2-(5,7-dimethyl-2-oxo-3a,4- dihydrothiazolo[4,5-b]pyridin-3-yl) acetohydrazide). Interestingly, T-7 demonstrated a weaker cytotoxic ef- fect towards leukemia and carcinoma cells compared to the parental compound T-1 (8 % inhibition of L1210 cells compared to 25 % by T-1 and 14 % of growth inhibition of MDA-MD-231 cells compared to 29 % by T-1). However, SK-MEL-28 cells were more sensitive to T-7 action compared to T-1 (47 % of growth inhi- bition compared to 13 % by T-1). Thus, the hydrazide group in N3-position of 5,7-dimethyl-3H-thiazolo [4, 5-b]pyridin-2-one is responsible for higher affinity of the T-7 compound to melanoma cells. For further evaluation of influence of other N3-po- sition substitutes in the T-2 molecule (5,7-dimethyl-6- [phenylazo]-3H-thiazolo[4,5-b]pyridin-2-one) aldehyde was conjugated to hydrazide of T-2 involving four- steps synthetic strategy. In contrast to the T-6 and T-7 compounds, which demonstrated higher affinity to me- lanoma cells, T-8 was more specific to leukemia cells – its cytotoxic effect was the same as of T-2 (61 % of growth inhibition compared to 65 % by T-2), while car- cinoma and melanoma cells were significantly more resistant to the T-8 action compared to T-2 (47 % of MDA-MD-231 cells compared to 82 % in case of T-2 and 48 % on SK-MEL-28 cells compared to 72 % in case of T-2). In conclusion, conjugation with aldehyde has not given any significant anticancer effect to T-2, which suggests that for preservation of the highest an- ticancer activity of T-2 scaffold (5,7-dimethyl-6-[phe- nylazo]-3H-thiazolo[4,5-b]pyridin-2-one) no substitu- tes should be placed at N3-position. Almost identical results were observed when a pro- pionic group was conjugated to N3-position of T-2 (5, 7-dimethyl-6-[phenylazo]-3H-thiazolo[4,5-b]pyridin- 2-one). The resulting compound T-9 was weaker than T-2 in all three tested cell lines (35 % growth inhibi- tion of L1210 cells compared to 65 % by T-2, 47 % of MDA-MD-231 cells compared to 82 % by T-2 and 43 % of SK-MEL-28 cells compared to 72 % by T-2). These results give an additional proof that no substitu- tes should be placed at N3-position for preservation of the highest anticancer activity of T-2 scaffold . The next part of the work was dedicated to study- ing the influence of different substitutes in C6-position of T-1 core scaffold. At the first step phenylazo frag- ment was reduced to amino group, and the resulting T- 10 compound completely preserved its anti-melanoma cytotoxic effect (72,5 % growth inhibition of SK- MEL-28 cells compared to 72 % by T-2), while its anti- carcinoma effect (52 % of growth inhibition of MDA- MD-231 cells compared to 82 % by T-2) and anti- leukemia activity (29 % of growth inhibition compared to 65 % by T-2) were significantly weaker than those of parental compound. Thus, the exchange of phenyl- azo group at C6-position for amino group somehow de- creases the affinity of 5,7-dimethyl-3H-thiazolo [4,5-b] pyridin-2-one scaffold to leukemia cells. A similar phe- nomenon was observed when cyano terminal motif in T-3 was hydrolyzed to acid in T-4, as mentioned before. The acylation of amino group at C6-position of T- 10 scaffold led to further decrease in its cytotoxic acti- vity – the resulting compound T-11 was weaker than its predecessor in carcinoma and melanoma cells (14 % growth inhibition of MDA-MD-231 cells compared to 52 % by T-10 and only 37 % inhibition of SK-MEL-28 melanoma cells compared to 72.5 % by T-10), while sensitivity of L1210 leukemia cells remained the same (30 % growth inhibition of L1210 leukemia cells com- pared to 29 % in case of T-10). Under the interaction of a product of acylation of aminogroup of T-10 by chloroacetylchloride with one of thiols, the T-12 compound was prepared. Interes- tingly, we observed a slight increase in anti-carcinoma effect of T-12 on MDA-MD-231 cells (66 % growth inhibition compared to 52 % effect of T-10), while its anti-leukemia action remained the same as of the paren- tal compound (34 % growth inhibition of L1210 cells compared to 29 % effect of T-10). In contrast to these data, SK-MEL-28 melanoma cells demonstrated decre- ased sensitivity to T-12 (34 % growth inhibition compa- red to 72.5 % by T-10). Thus, further steric modifica- tions decrease the anticancer potential of the amino- group at C6-position of the core scaffold and thus are not effective. 394 CHABAN T. I. ET AL. According to these results, several principal sugges- tions could be derived. Despite the introduction of va- rious substitutes into the 5,7-dimethyl-3H-thiazolo[4, 5-b]pyridin-2-one core molecule, we did not succeed in significant enhancement of their anticancer activity. The average cytotoxic activity of the most potent com- pound with anticancer activity T-2 (6-phenylazo-5,7- dimethyl-3H-thiazolo[4,5-b]pyridin-2-one) towards three cell lines was only 50 µM, which is still 10 times more than that of some clinically used anticancer drugs. Thus, further modifications in the structure of 6N-de- rivatives of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2- one should be done in order to enhance its anticancer potential, as well as to perform in-depth studies of its potential targets in tumour cells. Previously we repor- ted that conjugation of various side groups to 4-thiazo- lidone core could lead to the induction of different cell death pathways by such compounds [18]. However, in that case the chemical structure of substitutes had a lit- tle effect on the selectivity of action of these 4-thiazo- lidones toward leukemia and carcinoma cells. Here, one can see completely different situation, when ex- change of a single atom can lead to complete loss of the compound activity towards specific cell line (e. g., leu- kemia, carcinoma, melanoma). Such data indicate a dis- tinctive mechanism of action of thiazolo[4,5-b]pyridi- ne derivatives compared to the previously studied 4- thiazolidones. Conclusions. A few structure-functional relation- ships determining the anticancer potential of the 5,7-di- methyl-3H-thiazolo[4,5-b]pyridin-2-one derivatives could be drawn on a basis of the data obtained. The amino group at C6-position of core scaffold seems to be important for anti-melanoma activity of the resulting compound, while the phenylazo group at the same po- sition is responsible for a wider spectrum of cytotoxic activities. The biggest anticancer effect was observed under conjugation of the phenylazo group to C6-posi- tion of 5,7-dimethyl-3H-thiazolo[4,5-b]pyridin-2-one. None of used substitutes at N3-position alone had any significant effect which could be compared to that of the phenylazo group at C6-position. Thus, for further enhancement of the cytotoxic activity of T-2 , the addi- tional arylazo substitutes should be introduced into C6- position of this lead compound. Such experiments are in progress. Ò. ². ×àáàí, Ð. Ð. Ïàí÷óê, Î. Â. Êëåí³íà, Í. Ð. Ñêîðîõ³ä, Â. Â. Îãóðöîâ, ². Ã. ×àáàí Ñèíòåç òà âèâ÷åííÿ ïðîòèïóõëèííî¿ àêòèâíîñò³ äåÿêèõ ò³àçîëî[4,5-b] ï³ðèäèí³â Ðåçþìå Ìåòà. Ñèíòåçóâàòè ñåð³þ íîâèõ ïîõ³äíèõ 3H-ò³àçîëî[4,5-b]ï³ðè- äèí-2-îíó, ìîäèô³êóþ÷è ñòðóêòóðó áàçîâîãî ãåòåðîöèêëó çà 3-ì ³ 6-ì ïîëîæåííÿìè. Äîñë³äèòè ïðîòèïóõëèííó àêòèâí³ñòü îäåð- æàíèõ ñïîëóê in vitro íà äåÿêèõ ë³í³ÿõ çëîÿê³ñíèõ êë³òèí ññàâö³â. Ìåòîäè. Îðãàí³÷íèé ñèíòåç, ÏÌÐ-ñïåêòðîñêîï³ÿ, âèçíà÷åííÿ æèòòºçäàòíîñò³ êë³òèí çà ¿õí³ì çàáàðâëåííÿì òðèïàíîâèì ñè- í³ì. Ðåçóëüòàòè. Çàïðîïîíîâàíî çðó÷íèé ñèíòåòè÷íèé ï³äõ³ä ³ çíàéäåíî îïòèìàëüí³ óìîâè äëÿ ïðîâåäåííÿ ðåàêö³é îòðèìàííÿ 3H-ò³àçîëî[4,5-b]ï³ðèäèí-2-îí³â. Ðåàêö³ºþ [3 + 3] öèêëîêîíäåíñà- ö³¿ 4-³ì³íî-2-ò³àçîë³äîíó ç àöåòèëàöåòîíîì ³ �-ôåí³ëàçîàöåòèëà- öåòîíîì ó ñåðåäîâèù³ ìåòàíîëó çà ïðèñóòíîñò³ ìåòèëàòó íàò- ð³þ îäåðæàíî 5,7-äèìåòèë-3H-ò³àçîëî[4,5-b]ï³ðèäèí-2-îí ³ 6-ôå- í³ëàçî-5,7-äèìåòèë-3H-ò³àçîëî[4,5-b]ï³ðèäèí-2-îí, ÿê³ âèêîðè- ñòàíî ÿê âèõ³äí³ ðå÷îâèíè äëÿ ìàéáóòíüî¿ ñòðóêòóðíî¿ ìîäèô³- êàö³¿ áàçîâîãî ò³àçîëî[4,5-b]ï³ðèäèíîâîãî ãåòåðîöèêëó çà 3-ì ³ 6-ì ïîëîæåííÿìè. Ââåäåííÿì âèõ³äíèõ ñïîëóê ó ðåàêö³¿ ö³àíîåòè- ëþâàííÿ ç ïîäàëüøèì ã³äðîë³çîì îòðèìàíîãî ïðîäóêòó àëê³ëóâàí- íÿ, ÿêå â³äáóâàºòüñÿ ÷åðåç ñòàä³þ îäåðæàííÿ â³äïîâ³äíèõ êàë³é- íèõ ñîëåé, ç íàñòóïíèì ã³äðàçèíîë³çîì ïðîäóêò³â, à òàêîæ ó ðåàê- ö³þ â³äíîâëþâàëüíîãî ðîçùåïëåííÿ ç äàëüøèì àöèëþâàííÿì ïðî- äóêò³â îäåðæàíî ñåð³þ íîâèõ ïîõ³äíèõ 3H-ò³àçîëî[4,5-b]ï³ðèäèí- 2-îíó. Âèñíîâêè. Ò³àçîëî[4,5-b]ï³ðèäèí-2-îí ìîæíà ââàæàòè ïåðñïåêòèâíèì ìîëåêóëÿðíèì êàðêàñîì, ùî äîçâîëÿº çàñòîñîâó- âàòè çàçíà÷åíó êîíäåíñîâàíó ñèñòåìó äëÿ ðàö³îíàëüíîãî äèçàéíó ïîòåíö³éíèõ ë³êàðñüêèõ çàñîá³â ç øèðîêèì ñïåêòðîì ð³çíèõ âèä³â á³îëîã³÷íî¿ àêòèâíîñò³. Íàéåôåêòèâí³øèì âèÿâèëîñÿ ââåäåííÿ â 6-òå ïîëîæåííÿ ò³àçîëî[4,5-b]ï³ðèäèí-2-îíó ôåí³ëàçî çàì³ñíè- êà, ùî äàëî ìîæëèâ³ñòü óòðè÷³ ï³äâèùèòè éîãî ïðîòèïóõëèííèé ïîòåíö³àë. Êëþ÷îâ³ ñëîâà: ò³àçîëî[4,5-b]ï³ðèäèíè, [3+3] öèêëîêîíäåí- ñàö³ÿ, ñòðóêòóðíà ìîäèô³êàö³ÿ, ïðîòèïóõëèííà àêòèâí³ñòü. Ò. È. ×àáàí, Ð. Ð. Ïàí÷óê, Å .Â. Êëåíèíà, Í. Ð. Ñêîðîõèä, Â. Â. Îãóðöîâ, È. Ã. ×àáàí Ñèíòåç è èçó÷åíèå ïðîòèâîîïóõîëåâîé àêòèâíîñòè íåêîòîðûõ òèàçîëî[4,5-b]ïèðèäèíîâ Ðåçþìå Öåëü. Ñèíòåçèðîâàòü ñåðèþ íîâûõ ïðîèçâîäíûõ 3H-òèàçîëî[4,5- b]ïèðèäèí-2-îíà, ìîäèôèöèðóÿ ñòðóêòóðó áàçîâîãî ãåòåðîöèêëà â 3-ì è 6-ì ïîëîæåíèÿõ. Èññëåäîâàòü ïðîòèâîîïóõîëåâóþ àêòèâ- íîñòü ïîëó÷åííûõ ñîåäèíåíèé in vitro íà íåêîòîðûõ ëèíèÿõ çëîêà- ÷åñòåííûõ êëåòîê ìëåêîïèòàþùèõ. Ìåòîäû. Îðãàíè÷åñêèé ñèí- òåç, ÏÌÐ-ñïåêòðîñêîïèÿ, îïðåäåëåíèå æèçíåñïîñîáíîñòè êëå- òîê îêðàøèâàíèåì òðèïàíîâûì ñèíèì. Ðåçóëüòàòû. Ïðåäëîæåí óäîáíûé ñèíòåòè÷åñêèé ïîäõîä è óñòàíîâëåíû îïòèìàëüíûå óñëîâèÿ äëÿ ïðîâåäåíèÿ ðåàêöèé ïîëó÷åíèÿ 3H-òèàçîëî[4,5-b]ïè- ðèäèí-2-îíîâ. Ðåàêöèåé [3+3] öèêëîêîíäåíñàöèè 4-èìèíî-2-òèà- çîëèäîíà ñ àöåòèëàöåòîíîì è �-ôåíèëàçîàöåòèëàöåòîíîì â ñðå- äå ìåòàíîëà â ïðèñóòñòâèè ìåòèëàòà íàòðèÿ ïîëó÷åíû 5,7-äè- ìåòèë-3H-òèàçîëî[4,5-b]ïèðèäèí-2-îí è 6-ôåíèëàçî-5,7-äèìåòèë- 3H-òèàçîëî[4,5-b] ïèðèäèí-2-îí, êîòîðûå èñïîëüçîâàíû êàê èñ- õîäíûå âåùåñòâà äëÿ áóäóùåé ñòðóêòóðíîé ìîäèôèêàöèè áàçîâî- ãî òèàçîëî[4,5-b]ïèðèäèíîâîãî ãåòåðîöèêëà â 3-ì è 6-ì ïîëîæå- 395 SYNTHESIS AND EVALUATION OF ANTITUMOR ACTIVITY OF SOME THIAZOLO[4,5-b]PYRIDINES íèÿõ. Ââåäåíèåì èñõîäíûõ ñîåäèíåíèé â ðåàêöèè öèàíîýòèëèðîâà- íèÿ ñ ïîñëåäóþùèì ãèäðîëèçîì ïîëó÷åííîãî ïðîäóêòà àëêèëèðî- âàíèÿ, ïðîõîäÿùåãî ÷åðåç ñòàäèþ âûäåëåíèÿ ñîîòâåòñòâóþùèõ êàëèéíûõ ñîëåé, ñ äàëüíåéøèì ãèäðàçèíîëèçîì ïðîäóêòîâ, à òàê- æå â ðåàêöèþ âîññòàíîâèòåëüíîãî ðàñùåïëåíèÿ ñî ñëåäóþùèì àöèëèðîâàíèåì ïðîäóêòî ïîëó÷åíà ñåðèÿ íîâûõ ïðîèçâîäíûõ 3H- òèàçîëî[4,5-b]ïèðèäèí-2-îíà. Âûâîäû. Òèàçîëî[4,5-b]ïèðèäèí- 2-îí ìîæíà ñ÷èòàòü ïåðñïåêòèâíûì ìîëåêóëÿðíûì êàðêàñîì, ïîçâîëÿþùèì èñïîëüçîâàòü óêàçàííóþ êîíäåíñèðîâàííóþ ñèñòå- ìó äëÿ ðàöèîíàëüíîãî äèçàéíà ïîòåíöèàëüíûõ ëåêàðñòâåííûõ ñðåäñòâ ñ øèðîêèì ñïåêòðîì ðàçíûõ âèäîâ áèîëîãè÷åñêîé àêòèâ- íîñòè. Íàèáîëåå ýôôåêòèâíèì îêàçàëîñü ââåäåíèå â 6-å ïîëîæå- íèå òèàçîëî[4,5-b]ïèðèäèí-2-îíà ôåíèëàçî çàìåñòèòåëÿ, ÷òî äàëî âîçìîæíîñòü âòðîå ïîâûñèòü åãî ïðîòèâîîïóõîëåâûé ïî- òåíöèàë. Êëþ÷åâûå ñëîâà: òèàçîëî[4,5-b]ïèðèäèíû, [3 + 3] öèêëîêîí- äåíñàöèÿ, ñòðóêòóðíàÿ ìîäèôèêàöèÿ, ïðîòèâîîïóõîëåâàÿ àê- òèâíîñòü. REFERENCES 1. Lesyk R. B., Zimenkovsky B. 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