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Total Synthesis and Biological Evaluation of the Indoleamine 2,3-Dioxygenase Inhibitors Exiguamine A and Iso-Exiguamine A : 인돌아민 2,3-디옥시게나제 억제제 엑시구아민 에이와 아이소-엑시구아민 에이의 전합성 및 생물학적 평가
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- Authors
- Advisor
- 이철범
- Major
- 자연과학대학 화학부
- Issue Date
- 2018-08
- Publisher
- 서울대학교 대학원
- Description
- 학위논문 (박사)-- 서울대학교 대학원 : 자연과학대학 화학부, 2018. 8. 이철범.
- Abstract
- Described in this dissertation are total synthesis and biological evaluation of exiguamine A, an unprecedented alkaloid consisting of a hexacyclic skeleton. This marine natural product possesses potent inhibitory activity against the indoleamine 2,3-dioxygenase (IDO), which catalyzes the first and rate-limiting step of metabolic degradation of the essential amino acid tryptophan (Chapter 1). The immune-regulating enzyme IDO has emerged as a promising target for cancer immunotherapy as it is overexpressed in many human tumors and known to provide cancer cells with a mechanism to evade the immune system. Many endeavors have been made by our group and others to achieve biogenesis and chemical synthesis of exiguamine A (Chapter 2), and several synthetic pathways have been proposed. Our approach was based on the assembly of three domains – tryptamine quinone, dopamine, and hydantoin. Taking advantage of the redox equilibrium between quinone and hydroquinone, all subunits of exiguamine A were tethered in a convergent manner with concomitant construction of the core pyran framework though Mukaiyama-Michael and Claisen rearrangement reactions. After a series of cascade redox processes using hydrogen and oxygen, the efficient synthesis of exiguamine A was accomplished. Our synthetic route also allowed for the synthesis of an isomer of exiguamine A, named iso-exiguamine A (Chapter 3). The synthetic exiguamines were evaluated for IDO inhibitory activity in cell line (Chapter 4).
- Language
- English
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