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Quinonoid와 oxadiazolethione화합물의 합성 및 생리활성 연구

Title
Quinonoid와 oxadiazolethione화합물의 합성 및 생리활성 연구
Authors
채미진
Issue Date
2005
Department/Major
대학원 약학과
Publisher
이화여자대학교 대학원
Degree
Master
Abstract
가. Juglone, naphthazarin, naphthalene 1,4-dione 및 dimethyl cyclohexa-2,5-diene-1,4-dione 화합물 합성 Quinone 유도체들은 항진균, 항암, 항균, 항말라리아, nitric oxide synthase (NOS) 저해작용 등 여러 가지 생리활성을 나타낸다. 이에 본 연구에서는 quinone 유도체 중 유럽과 동양에서 오래 전부터 항암, 항염증, 상처치유, 항균, 항혈소판 작용이 있다고 보고 되어진 naphthazarin 유도체와 전보에서 소개된 5-hydroxy-1,4-naphthoquinone 유도체의 series와의 치환위치가 다른 구조 이성질체를 합성하여 그 항진균 작용을 검색 비교하였다. 또한 quinone 유도체 중 우수한 생리활성을 예상되는 naphthalene-1,4-dione과 cyclohexa-2,5-diene-1,4-dione 유도체를 새로이 합성하여 항진균 작용을 연구하였다. 5-Hydroxy-1,4-naphthoquinone 유도체들은 암세포에 대한 세포독성과 항 혈소판 작용이 우수하다고 알려진 juglone (5-hydroxy-1,4-naphthoquinone)에 선택적 치환반응을 위로 하기 이해 Br2로 bromination을 하여 새로이 모핵을 합성하였다. 그 후 당량의 다양한 arylthiols와 arylamin을 반응시켜 2-arylthio-5-hydroxy-1,4-naphthoquione (HNQSs) 유도체 9개와 2-arylamino-5-hydroxy-1,4-naphthoquinone (HMQNs) 유도체 5개를 얻었다. 5-Methoxy-1,4-naphthoquinone유도체들은 위와 마찬가지로 juglone을 methylation한 후, 선택적 치환반응을 유도하기 위해 bromination시켜 2-bomo-5-methoxynaphthalene-1,4-dione (MNQ)을 합성 후, 다양한 arylthiols을 반응 시켜 2-arylthio-5-methoxy-1,4-naphthoquinone (MNQSs) 유도 체 7개를 얻었다. 5,8-Hydroxy-1,4-naphthoquione 유도체들은 당량의 다양한 arylthiols 와 arylamines을 반응시켜 2-arylthio-5,8-dihydroxy-1,4-naphthoquinine (DHNQNs) 유도체 8개와 2-arylamino-5,8-dihydroxy-1,4-naphthoquinone (DHNQSs) 유도체 3개를 얻었다. Natphtalene-1,4-dione 유도체들은 우수한 항진균 작용이 있다고 보도된 1,4-naphthoquinone에 palladium(II) acetata를 이용해서 iodide 유도체를 치환 반응하여 2-arylnaphthalene-1,4-dione (NQIs) 유도체 5개를 얻었다. Dimethylcyclohexa-2,5-diene-1,4-dione 유도체들은 2,3-dimethylhydr Oquinone을 산화시킨 2,3-dimethyl-1,4-benzoquinone 에 palladium(II) acetate를 이용해서 iodide유도체를 치환 반응하여 5-4-aryl-2,3-dimethyl cyclohexa-2,5-diene-1,4-dione (DQIs) 유도체 5개를 얻었다. 나. 1,3,4-Oxadiazole-2(3)-thione 화합물 합성 항암, P-glycoprotein inhibitor로서 알려져 있는 genistein보다 우수한 작용이 있는 것으로 알려진 oxadiazolethione 유도체들의 다양한 생리활성에 대한 연구들이 많이 부족한 편이다. 따라서 기존에 발표된 oxadiazolethione 유도체들의 구조적 변형을 시도하여 동맥경화와 혈관 재협착의 원인이 되는 혈관평활근세포 (SMCs)의 증식 억제 작용을 검색하였으며 항진균 작용도 연구하였다. Oxadiazolethione 유도체들은 2,3-dicithylcyclohexa-2,5-diene-1,4-dione (NDOHs)에 당량의 다양한 arylhydrazide를 첨가하여 N’-(2,4-dimethyl-4-oxocyclohexa-2,5-dienylidene)-4-arylhydrazide (NHDHs) 중간체 6개를 합성한 후, 각각에 reduction시켜 N’-(4-hydroxy-2,3-dimethylphenyl)-4-arylhydrazide 중간체에 CSCl2를 이용해서 cyclization을 시도하여 3-(4-hydroxy-2,3-aryl)-5-p-tolyl-1,3,4-oxadiazole-2(3H)-thione (HDOTs) 유도체 6개를 얻었다. 이와 같은 방법으로 1,4-naphthoquinone을 출발물질로 cyclization을 시도하여 중간체5개와 3-(4-hydroxynaphthalen-1-yl)-5-aryl-1,3,4-oxadiazole-2(3H)thione (DOSs)유도체 2개를 얻었다. 다. 생리활성 평가 합성된 유도체 (NDOH01, NDOH-2, NDOH06, NHDH01, NHDH03, NHDH06, HDOT01, HDOT03, NOH02, NHD02)에 대해서는 Smooth muscle cells (SMCs)의 증식 저해 작용을 검색하였다. WST colorimeric assay에 의해 각 화학물의 IC50 값을 기준물질인 mycophenolic acid (MPA)와 비교하여 결정하였다. SMCs의 증식 저해작용을 검색한 결과 대부분의 oxadiazolethion유도체 및 중간체들의 활성은 MPA보다 우수하지 않은 것으로 나타났다. 합성한 유도체 (HNQSs, HNQNs, MNQSs, MNQNs, DHNQSs, DHNQNs, NQIs, DQIs, NDOHs , NHDHs, HDOTs)들에 대해서는 6가지 병원균주인 Candida albicans, Candida tropicalis, Candida krusei, Aspergillus niger, Aspergillus flavus, Cryptococcus neoformans 에 대하여 항진균 작용을 검색하였다. 각 화합물에 대한 MIC (minimum inhibitory condentration)는 액체 배지 희석법 (two fold broth dilution method)으로 하였고 대조 약물로는 fluconazole, flucytosine을 사용하였다. 최소 발육저지 농도, 즉 MIC (minimum inhibitory concentration)을 측정한 결과 대부분의 유도체에서 fluconazole 보다는 효과가 좋았다. 특히 HNQSs, MNQSs, NQIs, DQIs 유도체는 대부분이 C. albicans, C. tropicalis, C. krusei, A. niger, A.flavus, Cryptococcus neoformans에서 fluconazole보다 훨씬 효과가 좋았으나 flucytosine에서는 비슷하거나 효과가 좋지 않았다.;Naphthoquinone derivatives have been reported with various pharmacological effects such as antifungal, anticancer, and antimalarial activities. Especially, naphthazarin and juglone have been shown for their potent wound healing, antiinflammatory effect, antitumor, antimicrobial and antithrombotic activities. Based on these reports, I designed and synthesized new compounds, 2-bromo-5-hydroxynaphthalene-1,4-dione(HNQ), 2-bromo-5-methoxynaphthalene-1,4-dione (MNQ) and 2,3-dimethyl-1,4-bezoquinone (DQ), and evaluated their antifungal activities. 2-Arylthio-5-hydroxy-1,4-naphthoquione (HNQSs) and 2-arylamino-5-hydroxy-1,4-naphthoquinone (HMQNs) were obtained by the substitution of 5-hydroxynaphthalene-1,4-dione (HNQ) with the appropriate arylamines and arylthios. 2-Arylthio-5-methoxy-1,4-naphthoquinone (MNQSs) were obtained by the substitution of 2-bromo-5-methoxynaphthalene-1,4-dione (MNQ) with the appropriate arylthios. 2-Arylthio-5,8-dihydroxy-1,4-naph thoquinone (DHNQNs) and 2-arylamino-5,8-dihydroxy-1,4-naphtho quinone (DHNQSs) were obtained by the substitution of naphthazarin with appropriate arylamines and arylthios. 1,2-(Arylphenyl)naphthalene-1,4-dione (NQIs) were synthesized from the 1,4-naphthoquinone using appropriate iodide derivatives, as heck reaction method with palladium(II) acetate. 5-(4-Arylphenyl)-2,3-dimethylcyclohexa-2,5-diene-1,4-dione (DQIs) were obtained from the 2,3-dimethyl-1,4-bezoquinone (DQ) with the same method used for NQIs. The antifungal activities of HNQSs, HMQNs, MNQSs, NQIs and DQIs were evaluated using the two fold broth dilution method against C. albicans, C. tropicalis, C. krusei, A. niger and A. flavus. Their minimum inhibitory concentration (MIC) values were determined and compared with positive controls, fluconazole and fluorocytosine. among newly synthesized compounds, 2-(2-Fluorophenylthio)-5-hydroxynaphthalene-1,4-dione (HNQS02), 5-Hydroxy-2-(phenylthio) naphthalene-1,4-dione (HNQS08) showed relatively potent antifungal activities compared to fluconazole and flucytosine against C. tropicalis and C. krusei, and 2-(4-hydroxyphenyl) naphthalene-1,4-dione (NQI04), 2-(4-hydroxyphenyl)naphthalene-1,4-dione (NQI04) did against C. tropicalis and A.flavus. 1,3,4-Oxadiazole-2(3)-thione derivatives have been reported with various pharmacological activities such as anticancer and p-glycoprotein inhibitor. Therefore, I synthesized and tested various oxadiazolethione derivatives to elucidate their contribution to the antiproliferative effects on PDGF-stimulated SMC proliferation and to determine their MIC values. N-(2,4-dimethyl-4-oxocyclohexa-2,5-dienylidene)-4-arylhydrazide (NHDHs) were obtained by the 1,4-naphthoquinone with the appropriate arylhydrazide. N'-(4-hydroxy-2,3-dimethylphenyl)-4-arylhydrazide (NHDHs) were obtained by reduction of NHDHs with phenylhydrazine. 3-(4-Hydroxy-2,3-aryl)-5-p-tolyl-1,3,4-oxadiazole-2(3H)-thione (HDOTs) were synthesized by cylization of NHDHs with CSCl2. 4-Aryl-N'-(4-oxonaphthalen-1(4H)-ylidene)benzohydrazide (NOHs),N'-(4-hydroxynaphthalen-1-yl)-4-arylbenzohydrazide (NHDs) and 3-(4-hydroxynaph thalen-1-yl)-5-aryl-1,3,4-oxadiazole-2(3H)-thione (DOSs) were obtained via the same method. The derivatives (NDOH01, NDOH-2, NDOH06, NHDH01, NHDH03, NHDH06, HDOT01, HDOT03, NOH02, NHD02) from the series were tested for their antiproliferative effects on PDGF-stimulated SMC proliferation, which were determined by comparison with mycophenolic acid (MPA) as a standard agent.
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