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Синтез и цитотоксичность LSD1 ингибиторов

Работа №118400

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химия

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Год сдачи2019
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ПРИНЯТЫЕ СОКРАЩЕНИЯ 6
ВВЕДЕНИЕ 8
1. ЛЕТЕРАТУРНЫЙ ОБЗОР 9
1.1. Структура и функции LSD1 10
1.1.1. Структура LSD1 10
1.1.2. Функции LSD1 12
1.1.2.1. LSD1 как ко-репрессор транскрипции 13
1.1.2.2. LSD1 как ко-активатор транскрипции 13
1.1.2.3. LSD1 как деметилаза негистоновых белков 13
1.2. LSD1 и рак 14
1.2.1. LSD1 при раке молочной железы 14
1.2.2. LSD1 при раке простаты 15
1.2.3. LSD1 в AML 15
1.3. Методы скрининга для ингибиторов LSD1 16
1.3.1. Целевой анализ 18
1.3.2. Анализ на основе субстрата 19
1.3.3. Анализ на основе побочных продуктов 20
1.3.4. Анализ на основе ИЦП 20
1.4. Фармакологическое ингибирование LSD1 для терапии рака 21
1.4.1. Инактиваторы МАО и их производные 21
1.4.2. Натуральные продукты и их производные 22
1.4.3. Ингибиторы на основе пептидов 23
1.4.4. Ингибиторы на основе полиаминов 23
1.4.5. Металло-комплексные ингибиторы 24
1.4.6. Другие 25
1.5. Заключительные замечания и перспективы 25
2. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ 28
2.1. Синтез ингибиторов 28
2.2. Биологические испытания 31
3. ЭКСПЕРИМЕРТАЛЬНАЯ ЧАСТЬ 32
3.1. Реагенты и оборудование 32
3.3. Синтез целевого соединения 35
3.4. Биологические испытания 36
3.4.1. Культивирование клеток 36
3.4.2. Исследования цитотоксичности 36
ЗАКЛЮЧЕНИЕ
СПИСОК ИСПОЛЬЗУЕМОЙ ЛИТЕРАТУРЫ


Разработка новых подходов в терапии злокачественных новообразований является одной из важнейших задач современной медицинской химии. Особенных успехов в этом направлении за последние 20 лет удалось достигнуть с разработкой таргетной терапии, ориентированной на молекулярные механизмы в онкотрансформированных клетках. Несмотря на значительные успехи в этой области в последние годы отмечается резкий рост вторичной резистентности к таргетным противоопухолевым препаратом, что делает их использование в клинической практике затруднительным и требует разработки новых типов таргетных агентов. Несмотря на множество методологических подходов к преодолению вторичной резистентности одним из лидирующих подходов является создание таргетных ингибиторов дуального типа.
В представленной работе рассматриваются результаты исследований по изысканию новых дуальных ингибиторов, воздействующих на две важные биологические мишени участвующих в онкогенезе: EGFR - киназный домен эпидермального фактора роста и LSD1 - лизин специфическая гистон диметилаза.


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ДИПЛОМНЫЕ МАГИСТЕРСКИЕ ДИССЕРТАЦИИ
КУРСОВЫЕ СТАТЬИ ВКР

По результатам проделанной работы можно сделать следующие выводы:
1. На основе структурно-ориентированного молекулярного дизайна предложены новые эффективные дуальные ингибиторы ЕОБЯкиназы и LSD1 диметилазы, включающих 4-амино-5-(тиазол-2-ил)пиримидиновый скаффолд.
2. Посредством МТТ-теста показана высокая цитотоксичностьшуЛго
синтезированного соединения в отношении клеточных линий MCF-7, A549, A431 и SH- SY5Y в микромолярных концентрациях.
3. Показано, что высокая цитотоксичность на клеточных линиях сверэкспресирующих исследуемые мишение делает дальнейшее изучение механизма цитотоксического эффекта оправданным и актуальным.



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