Biopolym. Cell. 2020; 36(4):279-293.
Биоорганическая химия
Спироциклические тиенопиримидины: синтез, новая перегруппировка в условиях реакции Вильсмайера и in silico прогнозирование протираковой активности
1Ковтун А. В., 1Токарева С. В., 1Варениченко С. А., 1Фарат О. К., 2Мазепа А. В., 3, 4Доценко В. В., 1Марков В. И.
  1. Украинский государственный химико-технологический университет
    просп. Гагарина, 8, Днепр, Украина, 49005
  2. Физико-химический институт им. А. В. Богатского НАН Украины
    Люстдорфская дорога, 86, Одесса, Украина, 65080
  3. Кубанский государственный университет
    ул. Ставропольская, 149, Краснодар, Российская Федерация, 350040
  4. Северо-Кавказский федеральный университет
    ул. Пушкина, 1а, Ставрополь, Российская Федерация, 355017

Abstract

Цель. Поиск новых действенных противоопухолевых молекул среди легко доступных спироконденсированных тиено[2,3-d]пиримидинов. Методы. Органический синтез, спектральные методы и молекулярний докинг. Результаты. Были синтезированы спирогетероциклы конденсацией аминотиофенов с циклическими кетонами по реакции Гевальда. Следующие модельне соединения получены конденсацией 3-амино[2,3-b]пиридин-2-карбоксамидов с циклогексаноном в условиях кислотного катализа. Результаты докинга против киназы EGFRWT показали, что синтезированные соединения имеют хорошие энергии связывания в диапазоне от -8.4 до -10.2 ккал/моль. Среди исследованных соединений в качестве ингибиторов протеїн киназы СК2 7’,8’,9’,10’-тетрагидро-1’H-спиро[циклогексан-1,2’-пиримидо[4’,5’:4,5]тиено[2,3-b]хинолин]-4’(3’H)-он показал лучшую энергию связывания при наличии водородной связи с амикислотным остатком Val66. Также данное соединение показало лучшее результаты как потенциальный ингибитор B-Raf киназы. Выводы. Синтезированы новые спироконденсированные тиено[2,3-d]пиримидины. Изучена ингибирующая активность новых соединений в качестве потенциальных ингибиторов киназ EGFR, CK2, FGFR1 и B-raf. Показано, что спироконденсированные тиено[2,3-d]пиримидины перегруппировываются в производные тиено[2,3-d(b)]пиримидин(хинолина) под. действием реагента Вильсмайера-Хаака. Продукты перегруппировки в большинстве не образуют водородных связей с аминокислотными остатками и показывают умеренные энергии связывания. Отсутствие водородных связей продуктов перегруппировки не позволяет рекомендовать их для дальнейших исследований в отличие от спироконденсированных тиено[2,3-d]пиримидинов.
Keywords: тиено[2,3-d]пиримидины, тиено[2,3-b]пиридины, спирогетероциклы, реакция Вильсмайера-Хаака, молекулярный докинг, противораковая активность, ингибиторы киназ

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