Asymmetric synthesis of 3,4-dihydroxy-2-substituted pyrrolidines, possible glycosidase inhibitors

이진수 서강대학교 대학원 1999 국내박사

PART Ⅰ. Asymetric Synthesis of 3,4-Dihydroxy-2-Substituted Pyrrolidines, Possible Glycosidase Inhibitors Polyhydroxylated pyrrolidine, piperidine, 과 octahydroindolizidine들은 anti-HIV와 anticancer등으로 작용하는 glycosidase의 inhibitor로 알려져 최근에 많은 연구가 이루어지고 있다. 기존의 azasugar들의 합성은 sugar들을 출발물질로 매우 여러단계를 거쳐 낮은 수율로 합성되었다. 또한 natural한 sugar에서 제공되는 chirality를 그대로 유지해 합성하므로, 다양한 chiral isomer들을 합성 할 수 없었다. 본 연구에서 는 achiral한 2,3-dibromopropionate로 부터 출발해 chiral한 aziridine-2-carboxaldehyde를 합성하여 분리하고, wittig 반응을 통해 aziridine의 2위치에 선택적으로 trans형태의 αβ-unsaturated ester를 도입하고 osmium tetroxide와 작용해 dihydroxylation된 syn-diolisomer들을 합성하여 분리 하였다. 이 azirine 유도체를 pearlman catalyst존재하에 수소반응시켜, aziridine의 regioselective ring clevage와 이때 생성되는 amine과 ester의 intramolecular cyclization을 one-pot에서 동시에 거쳐 다양한 3,4-dihydroxy-2-methyl pyrrolidinone chiral isomer들을 sugar로 부터 합성한 것 보다 짧은 7단계를 거처 총수율 40%의 높은 수율로 합성할 수 있었다. PART Ⅱ. Synthesis and Structure-Activity Relationships of 2-Functionalized-1β-methylcarbapenem Antibiotics 페니실린이나 세파로스포린계 항생제에 비해 우수한 항균활성을 가지고 있으며 특히 내성균에 대해 탁월한 효과가 있어 차세대 항생제로 각광받고 있는 카바페넴계 항생제는 이미페넴과 메로페넴이 주사용 항생제로 개발되어 상품화 되어 있고 많은 연구가 이루어지고 있지만 아직까지 경구용 카바페넴은 상품화된 것이 없다. 본 연구에서는 경구용 카바페넴 항생제의 개발을 위해 1β-methylcarbapenem의 C2위치에 질소를 함유하는 여러 치환체를 도입하여 보기로 하였으며, 이를 위해 2-formyl-1β-methylcarbapenem 중간체로하여 여러가지 lactam 유도체들과 Aldol Reaction 또는 Wittig Reaction을 통하여 여러가지 락탐들을 카바페넴 C2 위치에 도입하였다. 이들 중 Aldol Reaction을 거쳐 만든 2α-lactamylhydroxy methycarbapenem 유도체들의 in vitro 항균력이 임상 3상에서 개발중인 선도물질 sanfetrinem을 능가하였고, dehydropeptidase-Ⅰ에 대해 안정하며 좋은 pharrnacokinetic data를 나타내었다. 또한 이들중 선택된 선도물질은 in vivo 항균력 (PD_(50)이 sanfetrinem보다 2~3배 이상 좋은 것으로 나타났다. 이 선도물질의 경구흡수도를 증가시키기 위하여 carboxylic acid group을 prodrug ester로 만들어 보았고, 그 중 cyclohexyloxycarbonyl ester유도체의 bioavalability가 경구용 카바페넴 sanfetrinem clexetile과 대등한 것을 알 수 있었다. PART Ⅰ. Asymmetric Synthesis of 3,4-Dihydroxy-2-Substituted Pyrrolidines, Possible Glycosidase Inhibitors Polyhydroxylated pyrrolidines, piperidines and octahydroindolizines (azasugars) have been shown to selectively inhibit the oligosaccharide processing enzymes known as glycosidases. Inhibitors of glycosidases are known to possess a variety of chemotherapeutic effect toward viral infection, tumor metastasis and metabolic disorders such as diabetes mellitus. The synthesis of azasugar is based on carbohydrate^(12) and non-carbohydrate starting materials, but those have difficulties such as lack of selectivities. Therefore, various synthetic routes starting from sugar or tartaric acid, chemoenzymatic and asymmetric synthetic strategies have been developed for the syntheses of azasugars in their optically active form. These synthetic pathways have low chemical yield and lengthy synthetic sequences. Our group recently reported that the C(3)-N bond of the aziridine-2-methanol derivatives could be reduced highly regioselective by a catalytic hydrogenation in the presence of the Pearlman's catalyst. Based on the previous results we envisaged a new efficient asymetric synthesis pathway to 3,4-dihydroxy-2-methylpyrrolidine by highly regioselective reductive ring cleavage of the aziridine, debenzylation, and intramolecular cyclization in one-pot. Therefore, 3,4-dihydroxy-2-methylpyrrolidines were synthesized from ethyl 2,3-dibromopropionate through 7 steps in an overall 40% yield. PART Ⅱ. Synthesis and Structure-Activity Relationships of 2-Functionalized-1β-methylcarbapenem Antibiotics. 2-Formyl-1β-methylcarbapenem can be used as a versatile intermediate to prepare potent 2-functionalized-1β-methylcarbapenem antibiotics. To date, only one method, was reported by shionogi group, described the oxidation of the 2-hydroxymethyl-1β-methylcarbapenem. A new approach to 2-formylcarbapenem is demonstrated by the key operation in the thiazole or 1,3-dithiane as a synthetic equivalent to the formyl group. Also, preliminary biological evaluation of 2-heterocyclic-1β-methylcarbapenems, were prepared using a similar synthetic method of 2-thiazolyl-1β-methylcarbapenem, was reported. In this thesis, the synthesis and biological activity of 1β-methyl-2-(α-functionalized) carbapenems were described. From these series, showed potent antibacterial activity against Gram-positive and Gram-negative bacteria, good stability to dehydropeptidase-I, and good pharmacokinetic data than those of sanfetrinem. As expected, in vivo antimicribial activity (PD_(50)) of these detivatives were better than these of sanfetrinem against Escherichia coli and streptococcus pyogenes. These compounds have been submitted for prodrug approach to optimize oral absorption. Through the investigation we have successfully obtained an oral active carbapenem, cyclohexyloxycarbonyl ester derivative.

國內外 IT클러스터 事例分析을 통한 成功的 IT클러스터 造成方案 硏究

이진수 成均館大學校 2004 국내석사

As borderless competition based on intergration of global market is rising up, the importance of competition predominance by continuous innovation has emerged. Owing to development of Information Technology, geographic borders between producers and consumers has been rapidly weekened. However, tendency of increasing gathering in order to share the information is a paradox. It is very dangerous for one company to take charge of whole technical development because of convergence between Information Technology and Bio Technology. Therefore, it is necessary to cooperate with big enterprises and small enterprises, companies and universities. Also, it is time for Korea to enhance its strong field and to find new growth engines such as RFID, IT SoC, post generation PC, etc. In order to do this, Korean government should adopt Cluster policy instead of typical industry policy before. However, the study on IT Cluster up to the present leave much to be desired. IT Cluster consists of five main factors localization, networking, embededness and institutional thickness, collective learning and innovative synergy. At first, amomg the successful foreign IT Clusters, I choose five cluster such as Silicon Valley, Oulu techno park, Kista science park, Taiwan and China clusters. I also analyzed the domestic IT clusters. The troubles of the domestic clusters are like this. Firstly, role classification among the players is obsecure. Secondly, there is only one-way or subordinate network. Thirdly, there is lack of close relationships in the organizations. Finally, the government focus on hardware method. On the other hand, key success factors for oversees IT clusters are like this. Firstly, stimulator's role is very important. Secondly, it is necessary for universities to encourage its power and to co-work with companies. Thirdly, taking account of characteristic cluster itself should be needed. Finally, government's industry policy should be changed into cluster policy. Based on above analysis, there are six key success factors for IT cluster - Vision of cluster, Promotion organization, Hard infra, Soft infra, Fundraising and Human capital. In summary, the most important thing is to get rid of the prejudice that the government is almighty. It is private sector or companies that are in charge of operating IT cluster and running business. It is hoped that this result might provide the useful guidelines for cluster researchers and policy makers. Forthermore, with this as a momentum, Korean government's industry policy should be changed into IT cluster policy instead of indivisual approaches.

回轉形狀 製品의 加工을 爲한 規則 基礎 準 創成形 工程計劃 시스템 開發

이진수 成均館大學校 1992 국내석사

意思疏通 能力向上을 위한 指導法 硏究

이진수 嶺南大學校 1993 국내석사

횡령죄와 배임죄의 경계획정에 관한 연구

이진수 서울대학교 대학원 2008 국내석사

SUV39H2 히스톤 메틸전이효소 유전자다형(1624G>C)과 폐암의 임상적 연관성에 관한연구

이진수 서울대학교 대학원 2007 국내박사

한국의 국가정책결정과정에서 사법부의 역할에 대한 연구

이진수 서울대학교 대학원 2006 국내석사

철도화물수송을 위한 최적 거점 네트워크 설계에 관한 연구

이진수 서울대학교 대학원 2006 국내석사

뮤추얼펀드 포트폴리오의 성과와 최적보유주식수준 및 최적펀드매니저수에 관한 실증연구

이진수 서울대학교 대학원 2006 국내석사

화학적 프로브로써의 바이오틴 혹은 광친화성 표지 화합물이 도입된 tanshinone 유도체의 합성과 생리활성에 관한 연구

이진수 성균관대학교 대학원 2006 국내석사

Tanshinones isolated from Salvia miltiorrhiza Bunge, a traditional Chinese medicinal herb are known to induce anti-inflammatory, antioxdative, and cytotoxic activity. Despite the biological activities the mechanism of action of tanshinones are remain unknown. In this study, we investigate synthesis and biological activities of tanshinone derivarives as chemical probe. Tanshinone IIB, 3-hydroxytanshinone IIA, tanshinone IIB were synthesized by the Snyder's method in several steps. When 3-hydroxytanshinone IIA was reacted with various carboxylic acid derivatives, esterification did not occur at all. Treatment of 3-hydroxytanshinone IIA with compound 70, however, ethylene glycol linker-introduced 3-hydroxytanshinone IIA derivative 72 provided in 68% yield. When tanshinone IIB was reacted with compound 75, spacer linker-introduced tanshinone IIB 77 was obitained in 98% yield. CF3-substitated diazirines 82 were prepared in 4 steps from CF3-substituted ketones 78 and photoaffinity probe 85 was obitained from compound 82b . The reactions of spacer linker-introduced tanshinone derivatives 72, 77 with biotin or compound 82b in the presence of DCC or EDCI afforded biotinylated or CF3-substituted diazirine moiety-introduced tanshinone derivatives 86, 87, 88, 89 respectively. These compounds can be utilized for evaluating for interaction with target proteins.