Quinone유도체 합성 및 생리활성 연구

Abstract

Quinolinedione, isoquinolinedione 유도체들은 항진균, 항균, 항암, 항말라리아, nitric oxide synthase inhibitor 작용이 있으며 naphthalenedione 유도체들은 항 혈액 응고, 항 혈전 효과가 있는 것으로 알려져 있다. 본 연구에서는 quinone 모핵에 halo, phenylamino, alkylamino 및 alkyl mercapto기 등이 치환되면 약효가 증가한다는 것에 착안하여 6-substituted-7-halo-5,8-quinolinedione, 2-substituted-3-halo-1,4-naphthalenedione을 합성하였다. 치환기로는 quinolinedione과 naphthalenedione의 전자 이동을 용이하게 해서 산화, 환원을 촉진시켜 강한 생리활성을 나타낼 것으로 기대되는 2,6-di-tert-but yl-4-hydroxyphenyl, 2,6-dimethyl-4-hydroxyphenyl, N,N-diethylanilino, N,N-di methylanilino기를 사용했고, 이미 약효가 좋은 것으로 보고된 amine들도 계속해서 사용하였다. 특별히 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-chloro -1,4-naphthalenedione은 알칼리 가수분해하여 2-(3,5-di-tert-butyl-4-hydrox yphenyl) -3-hydroxy-1,4-naphthalenedione를 합성하였다. 본 연구에서는 nitric oxide (NO)의 생리활성 연구에 널리 쓰이며 nitric oxide synthase (NOS) inhibitor로 작용하는 LY83583 (6-phenylamino-5,8-quinolinedio ne)과 유사한 7-arylamino-5,8-isoquinolinedione 유도체를 합성하였다. 치환체로 는 주로 fluoroaniline을 사용하였는데, 이것은 F가 LY83583의 H와 크기가 비슷하고 지용성을 증가시켜 생체 이용율을 높일 것으로 기대되기 때문이었다. 위에서 합성한 물질들에 대해서 생리활성을 검색하였다. Quinolinedione 물질에 대해서는 항진균성을 검색하였는데, 기대했던 것과는 달리 새로운 치환체를 도입해서 합성한 물질보다 기존에 보고되었던 6-arylamino-7-halo-5,8-quinolinedione이 효과가 좋은 것으로 나타났다. Naphthalenedione 계열의 물질에 대해서는 혈소판 응집 억제 작용을 검색하였는데, 예상했던 대로 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-halo-1,4-naphthalenedione이 효과 가 좋았다. NOS 저해성은 근이완 억제 정도로 측정하였는데, 새로 합성한 7-arylamino-5,8-isoquinolinedione보다는 전에 합성한 6-arylamino-5,8-quinol ionedione이, 그 중에서도 특히 6-[N-(2,3,4-trifluorophenyl)amino]-5,8-quinol inedione이 효과가 좋았다. ; Quinolinedione and isoquinolinedione derivatives are known for having antif ungal activities, cytotoxic effects and nitric oxide inhibitory effects. And naph thalenedione derivatives are reported to have anticoagulation and antithrombus effects. Therefore we synthesized quinone derivatives and evaluated them for their biological activities to search for new potential biological active agents. 6-Substituted-7-halo-5,8-quinolinedione and 2-substituted-3-halo-1,4-napht halenedione were synthesized. Substituents were 2,6-di-tert-butyl-4-hydrox yphenyl, 2,6-dimethyl-4-hydroxyphenyl, N,N-diethylanilino and N,N-dimethylan ilino groups because they are expected to activate quinolinedione and naphthal enedione by accelerating electron transfer. Also, we reported substituted quin one with arylamines already to have antifungal activities. 7-Arylamino-5,8-isoquinolinedione derivatives were synthesized. It was expected to be nitric oxide synthase (NOS) inhibitor, which may act as an isostere of LY83583(6-phenylamino-5,8-quinolinedione) used for study of nitric oxide physiological activity. Arylamine, substituent we used was fluoroaniline. As fluoro mimics the hydrogen of LY83583 and leads to increase lipid solubility, enhances rates of absorption and transport of drugs and inhibits metabolism. These new compounds synthesized were screened for physiological activities. 6-Arylamino-7-halo-5,8-quinolinedione had more potent antifungal activities than quinolinediones having new substitue nts. But as expected, 2-substituted-3-halo-1,4-naphthalenedione of which substituents were new compounds (2,6-di-tert-butylphenol, 2,6-dimethylphe nol) showed potent anticoagulation and antithrombus effects. In the test of NOS inhibitory effects, 7-arylamino-5,8-isoquinolinedione was little potent than 6-arylamino-5,8-quinolinedione which was synthesized before.