Каркасные и мостиковые фрагменты в дизайне физиологически активных веществ тема диссертации и автореферата по ВАК РФ 02.00.16, доктор химических наук Зефирова, Ольга Николаевна

• Зефирова, Ольга Николаевна
• доктор химических наук
• 2012

Оглавление диссертации доктор химических наук Зефирова, Ольга Николаевна

Введение 3

Глава Обзор литературы Использование каркасных и мостиковых структур в медицинской химии 4

Глава Применение каркасных и мостиковых фрагментов для создания упрощенных аналогов таксола 23

Глава Каркасная структура в создании лиганда «двойного действия» на тубулин и микротрубочки 83

Глава Стратегия увеличения липофильности соединения-лидера путем структурного «включения» в каркасный или мостиковый фрагмент 101

Глава Применение мостиковых группировок для ограничения конформационной подвижности мелатонина и серотонина

Глава Модификация соединения-лидера с двойной активностью с помощью мостиковой группировки 160

Экспериментальная часть 163

Выводы 294

Заключение диссертации по теме «Химия и технология композиционных материалов», Зефирова, Ольга Николаевна

выводы

1. Сформулированы принципы применения каркасных и мостиковых структур в создании физиологически активных веществ, в том числе 1) как биоизостерических группировок для сложных полициклических скелетов молекул, 2) как необычных фрагментов, ограничивающих конформационную подвижность структурных прототипов лекарственных веществ, 3) как увеличивающих липофильность неароматических моноциклических соединений при их «структурном» включении в каркас.

На этой базе в результате структурного дизайна и синтеза сфокусированных библиотек физиологически активных веществ на основе каркасных фрагментов выявлены новые соединения-лидеры для таких молекулярных мишеней как белок тубулин, рецепторы мелатонина и серотонина, ферменты синтаза оксида азота и инозитмонофосфатаза.

В ходе проведенных исследований получены следующие конкретные результаты для каждой биомишени.

2. Проведен молекулярный дизайн новых структурных классов упрощенных аналогов таксола, в которых полициклический скелет исходной молекулы заменен адаман-тановым или бицикло[3.3.1]нонановым фрагментом. Синтезирована библиотека таких веществ, представляющих собой сложные эфиры замещенных или незамещенных адаман-тановых и бицикло[3.3.1]нонановых спиртов с аминокислотой (2R,55)-Ы-бензоил- (или N-т/?ет-бутоксикарбонил)-(3-фенилизосерином.

Для полученных упрощенных аналогов таксола определены значения цитотоксич-ности по отношению к клеткам А459 (минимальное значение 1С5о=0.75цМ). Доказана способность некоторых соединений вызывать олигомеризацию тубулина, максимально высокую - для 1 -(ТЧ-бензоил-(З-фенилизосерилокси)адамантана. На основании исследований «структура-активность» продемонстрирована важная роль незамещенной адамантановой группировки и (27?,55)-Ы-бензоил-Р-фенилизосерина (но не позиции его присоединения к адамантану) в обеспечении высокой тубулин-олигомеризующей активности.

2. Предложена структура «упрощенного аналога» колхитакселя на основе колхицина и адамантанового «миметика» таксола и реализована многостадийная схема его получения. Синтезирован структурный аналог этого соединения колхадам, для которого доказано проявление цитотоксичности по отношению к различным штаммам опухолевых клеток in vitro в наномолярном интервале концентраций, а также продемонстрирована способность к увеличению продолжительности жизни экспериментальных животных с перевиваемым лимфолейкозом Р388 в экспериментах in vivo. У колхадама обнаружен уникальный, не описанный в литературе механизм противоопухолевого действия, а именно способность вызывать деполимеризацию микротрубочек с последующим образованием необычных тубулиновых кластеров. Представлено возможное объяснение этого механизма и продемонстрирована важная роль адамантанового каркаса в его обеспечении.

3. В работе предложена оригинальная стратегия увеличения липофильности моноциклических соединений-лидеров путем их «включения» в каркасный или мостиковый фрагмент, реализованная на примере создания структур потенциальных ингибиторов ферментов лшо-инозитмонофосфатазы и синтазы оксида азота.

Проведено тестирование синтезированных соединений in vitro и показано наличие слабой ингибирующей активности 2-гидрокси-1-адамантил фосфата натрия по отношению к инозитмонофосфатазе, а также выявлен ингибитор индуцибельной изоформы NO-синта-зы - 2-тиа-4-азабицикло[3.3.1]нон-3-ен-3-амин - перспективный кандидат для дальнейшего изучения его антигипотензивной и радиопротекторной активности in vivo.

4. Проведен молекулярный дизайн аналогов гормона мелатонина и нейромедиатора серотонина, в которых ограничение конформационной подвижности боковых цепей природных молекул достигается за счет включения в бициклические мостиковые группировки, аннелированные с индольным ядром.

Разработаны и реализованы эффективные многостадийные препаративные схемы синтеза целевых веществ с использованием в качестве ключевой стадии реакции Фишера.

Проведено тестирование полученных веществ in vitro и ex vivo и выявлен уникальный мостиковый аналог мелатонина с наномолярной активностью по отношению к МТ2 подтипу мелатониновых рецепторов.

5. В работе (независимо от фармацевтической компании Abbot, США) получен оригинальный мостиковый аналог известного антигистаминного препарата с нейропро-текторной активностью Димебона.

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