vestichИзвестия Национальной академии наук Беларуси. Серия химических наукProceedings of the National Academy of Sciences of Belarus, Chemical Series1561-83312524-2342The Republican Unitary Enterprise Publishing House "Belaruskaya Navuka"vestich-221Research ArticleОРГАНИЧЕСКАЯ ХИМИЯORGANIC CHEMISTRYCИНТЕЗ НОВЫХ 6-АЗАПИРИМИДИНОВЫХ 2′(3′)-ФТОРДЕЗОКСИНУКЛЕОЗИДОВSYNTHESIS OF NOVEL 6-AZAPYRIMIDINE 2′(3′)-FLUORODEOXY NUCLEOSIDESБожокТ. С.BozhokT. S.

науч. сотрудник

Senior Researcher

tboshok@tut.byКалиниченкоЕ. Н.KalinichenkoE. N.

член.-кор., д-р. хим. наук, зам. дир. по науч. и инновац. работе.

Corr. Member, Dr. Sc. (Chemistry), Deputy Director for scientific activity and innovations.

kalinichenko@iboch.bas-net.byИнститут биоорганической химии НАН БеларусиInstitute of Bioorganic Chemistry of the National Academy of Sciences of Belarus201617012017045159Copyright © Божок Т.С., Калиниченко Е.Н., 20172017Божок Т.С., Калиниченко Е.Н.Bozhok T.S., Kalinichenko E.N.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestichem.belnauka.by/jour/article/view/221

Биоизостерическая замена в молекуле биологически активного соединения – один из подходов, используемых в медицинской химии для создания более эффективных и безопасных лекарств. Введение атома фтора в биологически активные молекулы оказывает существенное влияние на их физико-химические и биологические свойства. Основные модификации, которые привели к обнаружению  фторпроизводных нуклеозидов с биологической активностью, включают замены во 2′- и 3′-положениях дезоксифуранозного цикла. В данной работе исследован подходк синтезу 1-(β-D-рибофуранозил)-6-азатимина и его новых 2′(3′)-фторсодержащих нуклеозидных аналогов путем конденсации 2,4-бис-О-триметилсилильного производного 6-азатимина с 1-О-ацетил-2,3,5-три-О-бензоил-β-D-рибофуранозой, 1-O-ацетил-2,5-ди-O-бензоил-3-дезокси-3-фтор-α,β-D-рибофуранозой или 3,5-ди-O-бензоил-2-дезокси-2-фтор-α-D-арабинофуранозил бромидом и последующим удалением защитных групп промежуточных N(1)-β-нуклеозидов под действием нуклеофильного агента. Наряду с основными продуктами реакции деблокированиявыделены их 5′-О-бензоильные производные. 2′(3′)-Фтордезоксинуклеозидные аналоги 5-метил-6-азацитозина получены прямым превращением 6-азатиминового фрагмента блокированных фтордезоксинуклеозидов в 6-азацитозиновый через соответствующие 4-тиопроизводные. Структура синтезированных нуклеозидов установлена на основании данных УФ-, ЯМР- и масс-спектроскопии. Таким образом, разработаны эффективные методы получения новых 2′(3′)-фторсодержащих нуклеозидных аналогов 6-азатимина и 5-метил-6-азацитозина, которые могут представлять интерес в качестве потенциальных противовирусных или противоопухолевых агентов.

Fluorinated nucleosides have been shown to possess interesting physicochemical and biological properties. Bioisosteric replacement of a hydroxy group or a hydrogen atom by fluorine atom(s) is a classic approach in medicinal chemistryto improve the pharmacological properties of a biologically active molecule. Essential modifications that led to the discovery of fluorinated nucleosides with biological activity are substitutions at 2′- and 3′-positions deoxy-furanosyl moiety. Novel 6-azathymine 2′(3′)-fluorodeoxy nucleosides have been prepared by the silyl method starting from persilylated 6-azathymine and 1-O-acetyl-2,5-di-O-benzoyl-3-deoxy-3-fluoro-α,β-D-ribofuranose or 3,5-di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabino-furanosyl bromide. Debenzoylation of protected 6-azathymine 2′(3′)-fluorodeoxy nucleosides with methanolic ammonia resulted in the corresponding fluorinated nucleosides in good yields. Along with the main products of the deprotection, their 5′-O-benzoyl derivatives were isolated. Conversion of the 6-azathymine 2′(3′)-fluorodeoxy nucleosides into 5-methyl-6-azacytosine 2′(3′)-fluorodeoxy nucleosides was accomplished via the corresponding 4-thioderivatives. The structures of all synthesized nucleosides were proved by UV-, NMR- and mass-spectroscopy. Novel 6-azapyrimidine 2′(3′)-fluorodeoxy nucleosides are of interest as potential antiviral and anticancer agents.

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The authors declare that there are no conflicts of interest present.