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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
DC Field | Value | Language |
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dc.contributor.advisor | 서영거 | - |
dc.contributor.author | 김태우 | - |
dc.date.accessioned | 2017-07-13T16:37:33Z | - |
dc.date.available | 2019-04-18 | - |
dc.date.issued | 2016-02 | - |
dc.identifier.other | 000000132415 | - |
dc.identifier.uri | https://hdl.handle.net/10371/120120 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 약학대학 약학과 약품제조화학전공, 2016. 2. 서영거. | - |
dc.description.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. | - |
dc.description.tableofcontents | I. Introduction 12
1. Introduction of STAT proteins 12 2. STAT3 and cancer 16 2-1. STAT3 as a molecular target for cancer treatment 17 2-2. STAT3 protein 17 2-3. Role of STAT3 in cancer 18 3. (-)-Galiellalactone 19 3-1. Biosynthetic process for (-)-galiellalactone 21 3-2. Previous synthetic approaches for (-)-galiellalactone 22 3-3. Previous SAR studies on (-)-galiellalactone 27 4. Pd(0)-catalyzed cyclization 28 4-1. Previous studies on Pd(0)-catalyzed cyclization 29 4-2. Synthetic applications of bridged bicyclic lactones 31 II. Results and Discussion 36 1. Enantioselective total synthesis of (-)-galiellalactone 36 1-1. Retrosynthetic analysis 36 1-2. Preliminary studies from known [2.2.1] bridged bicyclic lactone 37 1-3. Synthetic approach for cis-fused 5,5-bicyclic lactone intermediate 94 38 1-4. Revised retrosynthetic analysis for (-)-galiellalactone (1) 40 1-5. Preparation of allylic alcohol 107 41 1-6. Preparation of Pd(0)-catalyzed cyclization precursor 103a 43 1-7. Pd(0)-catalyzed cyclization of δ-valerolactone 103a 43 1-8. Synthesis of dihydroxy bicyclic lactone 97 and introduction of angular hydroxyl group. 47 1-9. Stereoselective crotylation of dihydroxy bicyclic lactone 94 48 1-10. Deoxygenation of secondary hydroxyl group 49 1-11. Ring-closing metathesis of bicyclic lactone 82a 51 1-12. Completion of total synthesis of (-)-galiellalactone 52 2. Syntheses and biological evaluation of (-)-galiellalactone and its analogues as STAT3 inhibitors in breast cancer cell lines 54 2-1. Syntheses of (-)-galiellalactone analogues 55 2-2. Biological evaluation of (-)-galiellalactone 57 2-3. Biological evaluation of (-)-galiellalactone analogues 60 III. Conclusion 62 IV. Experimental 63 V. Appendix 78 VI. References 101 VII. 국문초록 105 | - |
dc.format | application/pdf | - |
dc.format.extent | 4819599 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | (-)-Galiellalactone | - |
dc.subject | STAT3 | - |
dc.subject | Pd(0)-catalyzed cyclization | - |
dc.subject | cis-trisubstituted cyclopentane | - |
dc.subject | Riley oxidation | - |
dc.subject | Hosomi-Sakurai crotylation | - |
dc.subject.ddc | 615 | - |
dc.title | Enantioselective Total Synthesis of (-)-Galiellalactone and Biological Evaluation of Novel Galiellalactone-Based Analogues as STAT3 inhibitors | - |
dc.title.alternative | (-)-Galiellalactone의 입체선택적인 전합성 및 Galiellalactone 기반 STAT3를 저해하는 신규 유도체의 활성 연구 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Taewoo Kim | - |
dc.description.degree | Doctor | - |
dc.citation.pages | 105 | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2016-02 | - |
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