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Enantioselective Total Synthesis of (-)-Deguelin and Structure-activity Relationship (SAR) of Novel Hypoxia Inducible Factor-1α (HIF-1α) Inhibitors Targeting Retinal Neovascularization Disease
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 이지연 | - |
dc.contributor.advisor | 서영거 | - |
dc.contributor.author | 이승범 | - |
dc.date.accessioned | 2017-07-13T16:40:55Z | - |
dc.date.available | 2020-02-04T01:21:03Z | - |
dc.date.issued | 2017-02 | - |
dc.identifier.other | 000000142511 | - |
dc.identifier.uri | https://hdl.handle.net/10371/120169 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2017. 2. 서영거. | - |
dc.description.abstract | (-)-Deguelin is a natural rotenoid isolated from several botanical sources and has attracted much attention from biologists and chemists due to its promising anticancer and chemopreventive properties. Recently, we reported that deguelin interfered with ATP binding to Heat Shock Protein 90 (Hsp90), a protein associated with the stabilization and translocation of hypoxia inducible factor-1α (HIF-1α). First of all, we herein presented the enantioselective synthesis of (-)-deguelin accomplished through 12 steps from commercially available starting material, 3,4-dimethoxyphenol. The key features of our synthesis include the efficient preparation of the precursor for iterative cyclization via highly convergent assembly of two aromatic systems and facile construction of the cis-fused bisbenzopyran skeleton. Construction of the double cyclization precursor involves carbonylative epoxide ring opening catalyzed by cobalt and anionic aryl addition of two aromatic systems. The cis-fused bisbenzopyran skeleton was achieved by sequential Pd-catalyzed O- and C-arylation. The Pd-catalyzed O- and C-arylation were greatly improved in terms of yield and stereoselectivity compared to previous studies of asymmetric total synthesis of (-)-deguelin.
Another our effort was explanation of SAR for SH-42 and development of novel HIF-1α inhibitors targeting the retinal neovascularization disease. Ocular diseases featuring pathologic neovascularization are the leading cause of blindness. Anti-VEGF agents have been conventionally used for the diseases, however the treatment is reconsidered recently in the aspect that VEGF acts as a trophic factor. Accordingly regulating upstream of VEGF, such as HIF-1α has emerged as a desirable therapeutic target. We already identified a series of ring-truncated deguelin analogs that induce destabilization of HIF-1α on retina cell as well as cancer cell. Especially, the potent analog SH-42 exhibited suppressing effects in hypoxia-mediated retinal neovascularization and vascular leakage. We herein report a complete structure-activity relationship study of ring-truncated deguelin analogs, SH-42 on HIF-1α nano-luciferase activity inhibition. The analog SH-199 which contained 2-fluorobenzene ring in place of 3,4-dimethoxybenzene ring of SH-42 exhibited excellent in vitro HIF-1α inhibitory activity with an IC50 of 100 nM. Meanwhile, the analog SH-173 which has greatly improved water solubility showed significant HIF-1α inhibitory activity and anti-angiogenic effect comparable to the analog SH-42. Importantly, as SH-173 which has heteroatome-substituted benzene ring replacing the privileged chromene ring manifested the equipotent anti-angiogenic inhibitory activity on oxygen-induced retinopathy (OIR) model, a structural feature of the analog SH-173 was identified as a novel scaffold of HIF-1α inhibitors in lieu of the chromene ring. | - |
dc.description.tableofcontents | I. Introduction 1
1. Deguelin 1 1-1. Previous synthetic studies toward racemic deguelin 1 1-2. Previous asymmetric syntheses of (-)-deguelin 2 2. Heat Shock Protein 90 and Hypoxia-Inducible Factor-1 alpha 5 2-1. Hsp90 in cancer 6 2-2. HIF-1α regulation 7 3. Retinal Neovascularization Disease 10 3-1. Disease and therapies 10 3-2. Previous studies 15 II. Results and Discussion 17 1. Enantioselective total synthesis of (-)-deguelin 17 1-1. Retrosynthetic analysis 18 1-2. Preparation of first Pd-catalyzed cyclization precursor 19 1-3. First Pd-catalyzed cyclization and late-stage regioselective iodination 21 1-4. Endgame of asymmetric total synthesis of (-)-deguelin 22 2. Identification and application of representative Hsp90 inhibitor, SH-42 into cancer 24 2-1. Large scale synthesis of SH-42 24 2-2. Mechanism study of SH-42 26 2-3. Applications of SH-42 into cancer 27 2-3-1. Cytotoxicity of SH-42 for drug-nave cell lines 27 2-3-2. Xenograft model for SH-42 28 2-3-3. Reduced neuro toxicities induced by SH-42 29 3. Full SAR of novel HIF-1 inhibitors and application of the representative analog into retinal neovascularization disease 30 3-1. Modification of A-part analogs 32 3-2. Modification of B-part analogs 38 3-3. Modification of C-part analogs 40 3-4. Kinetic solubility of representative analogs 44 3-5. Anti-angiogenesis of representative chromene ring-truncated analog 45 3-6. Oxygen-inducible retinopathy model for representative analogs 46 III. Conclusion 48 IV. Experimental 49 V. References 75 VI. Appendix 84 VII. 국문초록 105 | - |
dc.format | application/pdf | - |
dc.format.extent | 3657175 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Asymmetric total synthesis | - |
dc.subject | Deguelin | - |
dc.subject | Pd-catalyzed α-arylation | - |
dc.subject | HIF-1α | - |
dc.subject | retinal neovascularization disease | - |
dc.subject | large scale synthesis | - |
dc.subject | tandem claisen condensation-decarboxylation-alkylation sequence | - |
dc.subject.ddc | 615 | - |
dc.title | Enantioselective Total Synthesis of (-)-Deguelin and Structure-activity Relationship (SAR) of Novel Hypoxia Inducible Factor-1α (HIF-1α) Inhibitors Targeting Retinal Neovascularization Disease | - |
dc.type | Thesis | - |
dc.description.degree | Doctor | - |
dc.citation.pages | x, 111 | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2017-02 | - |
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