Синтетический дизайн биологически активных соединений на основе моно- и бициклических производных циклогептана тема диссертации и автореферата по ВАК РФ 02.00.03, кандидат химических наук Хлевин, Дмитрий Андреевич

• Хлевин, Дмитрий Андреевич
• кандидат химических наук
• 2013

Оглавление диссертации кандидат химических наук Хлевин, Дмитрий Андреевич

Введение

1 Синтез и биологическая активность моно- и бициклических полиолов с 6 размером цикла 7-9 атомов (обзор литературы)

1.1. Синтез и биологическая активность производных 8- 6 оксабицикло [3.2.1 ] октана

1.1.1 Реакции [4+3] циклоприсоединения с производными фурана

1.1.2. Синтезы на основе реакции Дильса-Альдера с последующим 12 расширением цикла

1.1.3. Циклоприсоединение без участия фурана

1.1.4. Использование метатезиса

1.2. Методы синтеза моноциклических полигидроксипроизводных с размером 18 цикла 7-9 атомов

1.2.1. Окисление циклополиенов

1.2.2. Метатезис с замыканием цикла (RCM)

1.2.3. Внутримолекулярное циклоприсоединение нитронов к алкенам

1.2.4. Нуклеофильная циклизация

1.2.5. Свободнорадикальная циклизация и пинаконовое сочетание

1.2.6. Другие методы получения полиолов с 7- и 8-членным циклом

1.2.7. Синтез полигидроксициклононанов 31 1.3 Гликозидазная активность полиолов с размером цикла 7-8 атомов

2. Обсуждение результатов

2.1. Получение производных 8-оксабицикло[3.2.1]октана

2.2 Синтез структурных аналогов таксола и элеутеробина на основе оксабициклических каркасов

2.3. Синтез моноциклических производных циклогептана

2.4. Синтез ингибиторов ГМРаэе и лигандов 1шРЗ рецептора 66 2.5 Синтез ингибиторов гликозидаз на основе производных циклогептана

3. Экспериментальная часть

3.1. Методики синтеза и характеристики соединений

3.1.1. Синтезы исходных соединений

3.1.2. Восстановление дикетона (2) при действии ДИБАЛ-Н

3.1.3. Синтез дикетона (5)

3.1.4. Дехлорирование под действием цинковой пыли в уксусной кислоте

3.1.5. Восстановление дикетонов боргидридом натрия

3.1.6. Синтез кетоспирта (12)

3.1.7. Общая процедура дехлорирования а-хлоркетонов цинковой пылью в 85 уксусной кислоте

3.1.8. Общая процедура ацилирования бициклических спиртов уксусным 86 ангидридом

3.1.9. Общая процедура бензилирования спиртов

3.1.10. Общая процедура гидроксилирования двойной связи

3.1.11. Общая процедура эпоксидирования алкенов

3.1.12. Синтез сульфата (30)

3.1.13. Синтез трицикла (32)

3.1.14. Общая методика ацилирования спиртов (10) хлорангидридами 95 бензойных кислот

3.1.15. Общая методика этерификации спиртов с ЛА-метилурокановой кислотой

3.1.16. Синтез соединения (44)

3.1.17. Удаление оксазолидиновой защиты соединения (50)

3.1.18. Общая методика восстановительного раскрытия кислородного моста в 103 системе ДИБАЛ-Н/ДИБАЛ-С

3.1.19. Общая методика окисления органоаланов

3.1.20. Общая методика фосфорилирования спиртов

3.1.21. Общая процедура гидрирования бензиловых эфиров (удаление 110 бензильной защиты)

3.1.22. Синтез соединения (75)

3.1.23. Синтез соединения (77)

3.1.24. Синтез соединения (80)

3.1.25. Синтез соединения (82)

3.2. Молекулярное моделирование

3.3. Биотестирование 115 ВЫВОДЫ 119 Список использованных сокращений 120 Список цитируемой литературы

Введение диссертации (часть автореферата) на тему «Синтетический дизайн биологически активных соединений на основе моно- и бициклических производных циклогептана»

Полигидроксициклогептаны являются мало исследованным классом циклитов, во многом из-за их низкой синтетической доступности. Однако подобные соединения представляют большой интерес, поскольку могут проявлять широкий спектр физиологической активности: участвовать в процессах метаболизма углеводов, трансмембранном переносе, транспорте ионов в клетке.

Природные бициклические семичленные полиолы, алкалоиды тропанового ряда (8-азабицикло[3.2.1]октаны) являются селективными гликозидазными ингибиторами. Описан ряд их оксааналогов, проявляющих цитостатическую и противовирусную активность. Кроме того, фрагмент оксабициклооктана входит в состав ряда полициклических терпенов, например, диктиоксетана, энглерина и тромбоксана. Бициклические производные циклогептана могут быть использованы для синтеза упрощенных аналогов сложных природных молекул в рамках подхода ограничения конформационной подвижности, выступая в роли спейсеров для построения структур, содержащих одну или несколько фармакофорных групп.

Моноциклические производные циклогептана, в свою очередь обладают повышенной конформационной гибкостью, что облегчает встраивание в активные центры биомишеней и воспроизведение формы переходного состояния. У ряда производных гомоинозита, в первую очередь содержащих аминогруппы, была найдена выраженная ингибиторная активность в отношении гликозидаз, в ряде случаев превосходящая шестичленные аналоги. Наличие подобной активности позволяет рассматривать данные соединения как потенциальные лекарственные препараты для лечения сахарного диабета и вирусных инфекций. Подобные производные являются гидролитически стабильными, что во многих случаях делает их использование в составе лекарств более предпочтительным. Развитие исследований в данной области сдерживается отсутствием удобных методов синтеза семичленных циклитов заданной конфигурации.

С учетом большого потенциала полигидроксициклогептанов для медицинской химии, разработка стереоселективных методов синтеза этих соединений является весьма актуальной.

1. Обзор литературы. Синтез и биологическая активность моно- и бициклических полиолов с размером цикла 7-9 атомов

Полигидроксилированные соединения с размером цикла более 6 атомов встречаются в природе заметно реже, чем производные циклопентана и циклогексана, в большинстве случаев - в виде полициклических каркасных и конденсированных систем. Подобные соединения также являются синтетически труднодоступными, поскольку для создания семи- и восьмичленных циклов применяется довольно ограниченный набор синтетических методов [1,2]. Еще более сложной задачей является стереонаправленный синтез изомерных соединений, содержащих более трех ОН-групп определенной конфигурации. В настоящем обзоре литературы будут рассмотрены методы синтеза и биологическая активность двух типов соединений: бициклических полигидроксициклогептанов (производные 8-оксабицикло[3.2.1]октана) и моноциклических полиолов с размером цикла 7-9 атомов. Приведены наиболее общие методы создания соответствующих циклов, в том числе в полном синтезе сложных природных молекул, рассмотрены вопросы стереоселективности и проявления физиологической активности соединений. Отдельный раздел (1.3) посвящен анализу гликозидазной активности семи- и восьмичленных полиолов в сравнении с более изученными азациклитами (полигидроксиазепанами и азоканами).

Заключение диссертации по теме «Органическая химия», Хлевин, Дмитрий Андреевич

выводы

1. Предложен новый путь стереоселективного синтеза полигидроксилированных 8-оксабицикло[3.2.1]октанов.

2. Показана возможность синтеза трициклических оксетановых соединений (диокса-трициклононанов) - структурных аналогов природного терпена диктиоксетана.

3. Продемонстрирована возможность использования каркасных полиолов циклогептанового ряда как спейсеров для синтеза аналогов таксола и элеутеробина. Для полученных производных показана высокая аффинность к тубулину, цито- и митостатическая активность in vitro и in vivo.

4. На основе реакции восстановительного раскрытия кислородного моста 8-оксабицикло[3.2.1]октенов разработан метод получения моноциклических производных циклогептана. Впервые получены моно- и трифосфатные производные гомоинозита - перспективные ингибиторы инозитмонофосфатазы и лиганды инозиттрифосфатного рецептора.

5. Разработаны методы стереоселективного введения амино-группы в моно- и бициклические производные полигидроксициклогептанов. Показано, что полученные таким образом аналоги нортропановых алкалоидов являются эффективными гликозидазными ингибиторами.

Список использованных сокращений асас - ацетилацетонат В IN АР - бинафтил Вп - бензильная группа (PhCH2) Вое - бензилоксикарбонил Bz - бензоильная группа (PhCO)

Cbz - карбобензилокси-группа, бензилоксикарбонил (PhCH2OCO)

COD - циклооктадиенильная группа

DCM - дихлорметан, хлористый метилен

DMF (ДМФА) - диметилформамид

DMSO (ДМСО) - диметилсульфоксид dppb- 1,4-6ыо(дифенилфосфин)бутан

IC50 (ЕС50)- концентрация, вызывающая 50% ингибирование фермента или 50% проявление изучаемого эффекта (связывания и др.) IMPase - лшо-инозитмонофосфатаза

InsP3 - инозиттрифосфат, InsP3R - инозиттрифосфатный рецептор INAC - intramolecular nitrone-alkene cycloaddition, внутримолекулярное циклоприсоединение нитронов к алкенам m-CPB А - Aí-хлорпербензойная кислота Ms - мезил, метилсульфонил NMO - iV-оксид iV-метилморфолина NOE (ЯЭО) - ядерный эффект Оверхаузера Ру - пиридин

RCM - ring closing metathesis - метатезис олефинов с замыканием цикла rt (room temperature) - комнатная температура

TBS (TBDMS) - трет-бутилдиметилсилильная группа

TES - триэтилсилильная группа

Tf - трифлат, трифторметилсульфонил

TFA - трифторуксусная кислота

TMS - триметилсилильная группа

Ts - тозил, я-толуолсульфонил ц\¥ - микроволновое облучение

ДИБАЛ-Н (DIBAL-H) - диизобутиалюминийгидрид

ДМАП (DMAP) - н-диметиламинопиридин

ДЦК (DCC) - дициклогексилкарбодиимид

КССВ - константа спин-спинового взаимодействия ТГФ (THF) - тетрагидрофуран А - нагревание

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