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Part1: First total synthesis of natural iridoid lactone ; Part2: Cholesterol derived novel anti-apoptotic agent on the structural basis of ginsenoside Rk1
천연 iridoid lactone의 최초 전합성;Ginsenoside Rk1 구조 기반의 anti-apoptotic agent의 개발

DC Field Value Language
dc.contributor.advisor서영거-
dc.contributor.author이수진-
dc.date.accessioned2019-07-10T04:24:44Z-
dc.date.available2019-07-10T04:24:44Z-
dc.date.issued2011-08-
dc.identifier.other000000030977-
dc.identifier.urihttps://hdl.handle.net/10371/159099-
dc.identifier.urihttp://dcollection.snu.ac.kr:80/jsp/common/DcLoOrgPer.jsp?sItemId=000000030977ko_KR
dc.description학위논문 (박사)-- 서울대학교 대학원 : 제약학과, 2011.8. 서영거.-
dc.description.abstractCyclopentane system은 의약품 및 생리활성을 갖는 천연물에 광범위하게 존재하는 구조로서, 다양한 입체 선택적인 cyclopentane system의 합성법이 여러 연구자들에 의해 개발, 발전되어 왔다. Iridoid 화합물은 cis-fused cyclopentane system을 갖는 천연물의 통칭으로, 주로 약용 식물로 이용되던 천연 자원으로부터 다양한 구조의 iridoid가 보고되었다. 그 중 최근 분리, 보고된 (+)-6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1(3H)-one의 특징적인 구조와 생리활성에 대한 기대로, 전합성을 시도하였다.
본 연구실에서 개발한 intramolecular Pd(0)-catalyzed allylic alkylation을 응용하여 iridoid 화합물의 합성을 계획하였다. C4에 alkyl기를 도입하기 위해 trisubstituted allyl carbonate가 도입된 γ-lactone을 합성 전구체로 계획하였다. 이를 합성하기 위해 합성 효율성이 높은 silicon-tether를 이용한 분자내 ring closing metathesis를 수행하였고, Pd(0)-catalyzed cyclization을 수행해 좋은 수율과 입체 선택적으로 bicyclic lactone을 합성하였다. 또한 이를 추가로 변환하여 iridoid의 핵심 골격인 cis-fused cyclopentane system을 효율적으로 합성하였다. C7-Hydroxymethyl을 입체선택적으로 도입하고자 cyclopentenol에 silicon-tether를 이용한 intramolecular radical cyclization, Tamao-Fleming oxidation을 수행하여 효과적으로 합성을 완료하였다.
본 연구를 통해 본 연구실에서 개발한 substituted vinyl기가 도입된 bicyclic lactone을 중간체로 이용하여 천연물의 합성에 적용할 수 있음을 확인하였고, 향후에 다양한 생리활성을 갖는 iridoid, iridoalkaloid등의 천연물 합성에 응용할 수 있을 것이라 기대한다.
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dc.description.abstract혈관 내벽은 혈관내피세포의 단일막으로 이루어져 있다. 혈관 내피세포의 항상성 유지가 혈관의 생명활동을 유지하는 중요한 요인이다. 혈관내피세포의 세포사멸에 의한 혈관의 구조변화와 기능저하가 동맥경화, 동종이식편에 의한 맥관장애, 울혈성 심부전 등의 여러 질병과 연관된다는 연구결과가 보고되고 있다. 따라서 혈관내피세포의 세포사멸 억제제가 혈관질환의 새로운 치료제로서 연구 가치가 있으리라 생각된다.
최근, 인삼으로부터 분리 보고된 ginsenoside Rg3, Rk1이 세포사멸 억제효과가 있는 것으로 발표되었다. 하지만 이들 ginsenoside들은 다당체를 함유하고 있어 산성 조건에서 화학적으로 불안정하고, 자연에서 얻기에는 양적인 면에서 한계가 있기 때문에 이들 구조를 기반으로 하여 화학적으로 비교적 안정하면서 세포사멸 억제효과를 갖는 유도체들의 합성을 계획하였다. Ginsenoside의 뼈대인 스테로이드 골격을 유지하면서 ginsenoside의 활성을 유지할 수 있는 여러 phytosterol을 검색하였고, C3 hydroxyl기에 활성에 중요한 역할을 하는 glucoside를 대체할 bioisoster를 도입하고자 하였다. 이를 통해 상업적으로 손쉽게 구입 가능한 콜레스테롤을 기반으로 하여 다양한 유도체를 합성하였고, 이들의 세포사멸억제 효과를 확인하였다.
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dc.description.abstractIridoids are a large family of natural monoterpenoids products, and structurally characterized by a cis-fused cyclopenta[c]pyran ring system. The unique cis-fused cyclopenta[c]pyran ring system has presented a variety of challenges for chemical synthesis and in the analysis of biological activities. In particular, we have been interested in a recently reported iridoid lactone, which is structurally related to loganin and consists of a C7-substituted C6-hydroxycyclopenta[c]lactone.
Iridoid lactone, (+)-6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1 (3H)-one, was isolated from the roots and rhizomes of Nardostachys chinensis Batalin (Valerianaceae). This plant has been used as a Chinese folk medicine and its roots and rhizomes exhibit a variety of biological activities, such as sedative, antimalarial, antinociceptive, cytotoxic, and enhancement of nerve growth factor activities. Thus, the unique structural feature as well as the unknown biological activity of iridoid lactone led us to synthesize the recently reported iridoid lactone.
In this connection, we accomplished the first total synthesis of (+)-6-hydroxy-7- (hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1 (3H)-one (1) in 13 steps. The key features of the synthesis involve the stereoselective and efficient preparation of the bicyclic lactone via Pd(0)-catalyzed cyclization, which is easily transformated to cyclopentanol intermediate and then the silicon-tethered radical cyclization followed by Tamao-Fleming oxidation for the stereoselective introduction of the C7-hydroxymethyl substituent. This versatile synthetic approach is expected to be widely utilized for the synthesis of iridoids and iridoalkaloids.
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dc.description.abstractThe endothelial cell monolayer constructs the lining of the blood vessel. In this particular position, different stimuli activate a cascade of proteases (caspases) that execute a program of cellular self-destruction by cleaving cellular structures at specific sites in a strictly controlled manner. This leads to the disassembly of the cell into small apoptotic bodies without spillage of cellular contents or significant inflammatory responses.
Recently, some ginsenosides isolated from P. ginseng have represented the anti-apoptotic activities on HUVECs. However, ginsenosides are generally labile under acidic conditions. And the compositions of ginsenosides in ginseng are variable depending on the growth environment, growth period, and process of extraction. In this connection, we planned to synthesize the antiapoptotic agents from the simple and easily accessible phytosterol derivatives.
We discovered that the glucosyl moiety at C3 hydroxyl group is essential for anti-apoptotic activity through the comparison of some ginsenosides. We first searched the proper phytosterol for the replacement of the ginsenoside triterpene backbone. In particular, cholesterol, which has the linear side chain at C24, was the best choice. Then, the diverse bioisoster of glucosyl moiety at C3 hydroxyl group was substituted. Cyclic ether, acyclic ether, and spatial interactive bulky substituents were adapted to the C3 hydroxyl group.
With those analogs in hand, we tested the MTT assay on HUVECs. Throughout, the analogs 7 and 9 possessing the cholesterol scaffold and the cyclic carbohydrate equivalents exhibited excellent cell survival activities, which are equipotent to that of ginsenoside Rk1. In addition, these analogs exhibited dose-dependent cell viability on the HREC line. The excellent human EC protective activities of our novel Rk1-based anti-apoptotic agents allow us to envisage their valuable application for the treatment of vascular disorders. Currently, systematic studies on their therapeutic applications, including in vivo testing of the potent sterol analogs as well as their mechanistic aspects, are in good progress.
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dc.format.extentix, 99 장, vii, 67 장-
dc.language.isoeng-
dc.publisher서울대학교 대학원-
dc.subject(+)-6-hydroxy-7-(hydroxymethyl)-4-methylenehexahydrocyclopenta[c]pyran-1 (3H)-one-
dc.subjectiridoid lactone-
dc.subjectiridoid-
dc.subjectPd(0)-catalyzed cyclization-
dc.subjectbicyclic lactoen-
dc.subjectsilicon-tethered radical cyclization-
dc.subjectTamao-Fleming oxidation-
dc.subject혈관내피세포-
dc.subject세포사멸-
dc.subject동맥경화-
dc.subject동종이식편에 의한 맥관장애-
dc.subject울혈성 심부전 ginsenoside Rg3-
dc.subjectRk1-
dc.subjectphytosterol-
dc.subject콜레스테롤-
dc.subject세포사멸 억제효과-
dc.subjecthuman endothelial cell-
dc.subjectapoptosis-
dc.subjectcholesterol derivatives-
dc.subjectginsenoside Rg3-
dc.titlePart1: First total synthesis of natural iridoid lactone ; Part2: Cholesterol derived novel anti-apoptotic agent on the structural basis of ginsenoside Rk1-
dc.title.alternative천연 iridoid lactone의 최초 전합성;Ginsenoside Rk1 구조 기반의 anti-apoptotic agent의 개발-
dc.typeThesis-
dc.typeDissertation-
dc.description.degreeDoctor-
dc.contributor.affiliation제약학과-
dc.date.awarded2011-08-
Appears in Collections:
College of Pharmacy (약학대학)Dept. of Manufacturing Pharmacy (제약학과)Theses (Ph.D. / Sc.D._제약학과)
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