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Enantioselective Total Synthesis of (-)-Galiellalactone and Biological Evaluation of Novel Galiellalactone-Based Analogues as STAT3 inhibitors
(-)-Galiellalactone의 입체선택적인 전합성 및 Galiellalactone 기반 STAT3를 저해하는 신규 유도체의 활성 연구

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Authors
김태우
Advisor
서영거
Major
약학대학 약학과
Issue Date
2016-02
Publisher
서울대학교 대학원
Keywords
(-)-GaliellalactoneSTAT3Pd(0)-catalyzed cyclizationcis-trisubstituted cyclopentaneRiley oxidationHosomi-Sakurai crotylation
Description
학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과 약품제조화학전공, 2016. 2. 서영거.
Abstract
(-)-Galiellalactone (1), a fungal metabolite originally isolated from the Galiella rufa in 1990, has been reported to be a potent and specific inhibitor of signal transducer and activator of transcription 3 (STAT3), which is involved in numerous signaling pathways. (-)-Galiellalactone covalently binds to one or more cysteine residues in STAT3 and subsequently blocks the DNA binding of phosphorylated STAT3 without inhibition of phosphorylation and dimerization. (-)-Galiellalactone also induces apoptosis and growth inhibition of human prostate cancer cells expressing constitutively active STAT3 both in vitro and in vivo. For these reasons, (-)-galiellalactone has recently been considered to be a potential therapeutic agent against hormone-refractory prostate cancer.
First, we have accomplished an enantioselective total synthesis of (-)-galiellalactone. The key features of our synthesis involve the highly stereoselective construction of the cis-trisubstituted cyclopentane intermediate by a Pd(0)-catalyzed cyclization, the stereospecific introduction of an angular hydroxyl group by Riley oxidation, and the efficient construction of the tricyclic system of (-)-galiellalactone via a combination of diastereoselective Hosomi-Sakurai crotylation and ring-closing metathesis (RCM). Next, we applied the synthetic strategy established in a process of total synthesis of (-)-galiellalactone into the syntheses of tricyclic or bicyclic galiellalactone analogues. In the present study, we investigated the inhibitory effects of (-)-galiellalactone and its structure variants on STAT3 activation and its applications in TNBC (triple-negative breast cancer) cells.
Language
English
URI
https://hdl.handle.net/10371/120120
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College of Pharmacy (약학대학)Dept. of Pharmacy (약학과)Theses (Ph.D. / Sc.D._약학과)
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