Производные нуклеиновых кислот, содержащие модифицированные звенья 2'-О-алкильного типа: 2'-аминокислотные и 2'-альдегидные олигонуклеотиды тема диссертации и автореферата по ВАК РФ 02.00.10, кандидат химических наук Казанова, Евгения Викторовна

• Казанова, Евгения Викторовна
• кандидат химических наук
• 2010

Оглавление диссертации кандидат химических наук Казанова, Евгения Викторовна

1. УСЛОВНЫЕ СОКРАЩЕНИЯ

2. ВВЕДЕНИЕ

3. ИНГИБИРОВАНИЕ РАЗЛИЧНЫХ СТАДИЙ СИГНАЛЬНОГО КАСКАДА ФАКТОРА ТРАНСКРИПЦИИ №-кВ С ПОМОЩЬЮ НИЗКОМОЛЕКУЛЯРНЫХ СОЕДИНЕНИЙ И ФРАГМЕНТОВ НУКЛЕИ1ЮВЫХ КИСЛОТ (ОБЗОР ЛИТЕРАТУРЫ)

3.1. Введение

3.2. Биологические функции фактора №-кВ

3.3. Сигнальные пути активации фактора ОТ-кВ

3.4. ЫБ-кВ как редокс-чувствительный фактор транскрипции

3.5. №-кВ и воспалительные процессы

3.6. Активация ОТ-кВ, злокачественное перерождение клеток и апоптоз

3.7. Низкомолекулярные ингибиторы активности №-кВ

3.7.1. Низкомолекулярные ингибиторы №-кВ, обладающие противовоспалительными и антиоксидантными свойствами

3.7.2. Сулиндак и его метаболиты

3.7.3. Циклопентеноновые простагландины

3.7.4. Флавоноиды и фенольные соединения

3.7.5. Биологически активные компоненты микроорганизмов и растений и их синтетические аналоги

3.7.6. Глюкокортикоидные ингибиторы

3.7.7. Ингибиторы протеосомы

3.7.8. Алкилируюицие реагенты

3.8. Олигонуклеотидные ингибиторы ОТ-кВ

3.8.1. Антисмысловые олигонуклеотидные ингибиторы ЫР-кВ

3.8.2. Олигонуклеотидные ингибиторы-рибозимы

3.8.3. Ингибиторы №-кВ на основе з1РНК

3.8.4. Олигонуклеотидные ингибиторы, образующие тройные спирали с кВ-участками

3.8.5. Олигонуклеотидные ингибиторы-«ловушки» субъединиц фактора транскрипции №-кВ

Заключение диссертации по теме «Биоорганическая химия», Казанова, Евгения Викторовна

6. ВЫВОДЫ

1. Разработан новый эффективный метод синтеза З'-амидофосфитов 2'-аминокислотных производных уридина:

- аллилового эфира Л/а-{2-[3'-0-(А^,//-диизопропиламино-2-цианэтокси-фосфинил)-5,-0-(4,4'-диметокситритил)уридин-2'-0-ил]этокси}карбонил-Ь-фенилаланина,

- метилового эфира А/а-{2-[3'-0-(Л^,А^-диизопропиламино-2-цианэтоксифосфинил)-5'-0-(4,4'-диметокситритил)уридин-2'-0-ил]этокси}карбонил-А^т-тритил-Ь-гистидина,

- метилового эфира А'а-{2-[3'-0-(Аг,Л^диизопропиламино-2-цианэтоксифосфинил)-5'-0-(4,4'-диметокситритил)уридин-2'-0-ил]этокси}карбонил-А'Е-(9-флуоренилметокси-карбонил)-Ь-лизина.

С использованием этих соединений были синтезированы олигонуклеотиды, содержащие 2'-аминокислотные производные уридина.

2. Показано, что 2'-аминокислотные производные олигонуклеотидов обладают способностью гидролизовать модельные РНК-субстраты в выбранных условиях.

3. Изучены свойства олигонуклеотидов, содержащих остатки 2'-<9-[2-(2,3-дигидроксипропил)амино-2-оксоэтил]уридина, как лигапдов субъединиц р50 и р65 фактора транскрипции ОТ-кВ. Определены оптимальные условия образования специфических комплексов фрагментов НК с субъединицами транскрипционного фактора.

4. Сравнительное исследование химических свойств фрагмешов ДНК, содержащих остатки 2'-0-(2,5-диоксо-3-азапентил)уридина и 2'-0-(2-оксоэтил)уридина, показало, что оксоэтильные производные обладают более высокой реакционной способностью в условиях ковалентного связывания с НК-узнающими белками. Продемонстрирован неспецифический характер взаимодействия 2'-оксоэтильных и 2'-диоксоазапентильных производных с субъединицами р50 и р65 фактора транскрипции ЫР-кВ.

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