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Синтез и цитотоксическая активность производных азаиндола

Работа №108992

Тип работы

Бакалаврская работа

Предмет

химия

Объем работы78
Год сдачи2019
Стоимость4275 руб.
ПУБЛИКУЕТСЯ ВПЕРВЫЕ
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ПРИНЯТЫЕ СОКРАЩЕНИЯ 6
ВВЕДЕНИЕ 9
1. ЛИТЕРАТУРНЫЙ ОБЗОР 10
1.1 Введение 10
1.2 Азаиндолы как ингибиторы киназ 13
1.2.1 Ингибиторы ALK киназы 13
1.2.2 Ингибиторы Aurora киназы 13
1.2.3 Ингибиторы Cdc7 17
1.2.4 Ингибиторы CHK1 22
1.2.5 Ингибиторы с-Met киназы 23
1.2.6 Ингибиторы DYRK1A киназы 25
1.2.7 Ингибиторы FAK 28
1.2.8 IKK2 ингибиторы 28
1.2.9 Ингибиторы JAK2 30
1.2.10 Двойные ингибиторы KIT/FMS киназы 32
1.2.11 Ингибиторы PAK1 киназы 33
1.2.12 Ингибиторы p38a MAP киназы 34
1.2.13 Ингибиторы Р1Мкиназы 37
1.2.14 Ингибиторы PI3 киназы 38
1.2.15 Ингибитор B -Raf киназы 39
1.2.16 Ингибиторы Rho-киназы (ROCK) 40
1.2.17 Ингибитор m-TORкиназы 42
1.2.18 Ингибитор ТгкАкиназы 44
1.2.19 Способ связывания азаиндола 45
1.2.20 Натуральные продукты как ингибиторы киназы 48
2. РЕЗУЛЬТАТЫ И ИХ ОБСУЖДЕНИЯ 57
2.1 Синтез ингибитора 57
2.2 Биологические испытания 59
3. ЭКСПЕРИМЕНТАЛЬНАЯ ЧАСТЬ 60
3.1 Реагенты и оборудование 60
3.2 Синтез целевых соединений 61
3.3 Биологические испытания 63
3.3.1 Культивирование клеток 63
3.3.2 Исследования цитотоксичности 63
ВЫВОДЫ 645
СПИСОК ИСПОЛЬЗУЕМОЙ ЛИТЕРАТУРЫ 66


Производные азаиндола занимают важное место в медицинской химии, потому что обладают биологической активностью. Они проявляют антионкогенную, противоопухолевую и антибактериальную активность. К сожалению, такие болезни как онкология и туберкулез остаются серьёзной проблемой здравоохранения во всем мире. Поэтому для повышения эффективности лечения этих заболеваний требуются новые лекарства и терапевтические стратегии. До сих пор ведутся активные поиски новейших, более эффективных и безопасных лекарственных веществ с азаиндолным скаффолдом [1]. На данный момент наиболее значимым противоопухолевым средством является препарат вемурафениб, продаваемый как Зельбораф[2].
На основании вышеизложенного, вполне очевидно, что синтез новых комбинаторных библиотек низкомолекулярных производных азаиндола с последующим скринингом их биологической активности является крайне актуальной задачей.
Целью настоящей работы является разработка синтетического подхода к получению полифункциональных азаиндолов в качестве ингибиторов протеинкиназ.
Для успешной реализации цели были сформулированы следующие задачи:
1. Разработать синтетическую методологию получения производных3-(1,2,3,6- тетрогидропиридин-4-ил)-1#-пирроло[2,3-й]пиридина;
2. Синтезировать библиотеку данных производных азаиндола;
3. Исследовать цитотоксичность представителей синтезированной комбинаторной библиотеки в отношении клеточной линии сверэкспресирующих EGFR киназу.


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По результатам проделанной работы можно сделать следующие выводы:
1. Осуществлён синтез азаиндольного MAPK-ингибитора с хорошим выходом. Показана возможность эффективного использования оксона для оксиления пиримидинсодержащих сульфидов.
2. Посредством МТТ-теста показана высокая цитотоксичность invitro синтезированного соединения в отношении клеточных линий, сверхэкспаресирующих MCF-7, A549 и A431 в микромолярных концентрациях.
3. Показано, что высокая цитотоксичность на клеточных линиях сверэкспресирующих рецептор эпидермального фактора делает дальнейшее изучение механизма цитотоксического эффекта обусловленного мультитаргетным эффектом оправданным и актуальным.



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