Isolation and Characterization of New Sirtuin1 (SIRT1) Activators from Medicinal Plants

Abstract

Silent information regulator two ortholog 1 (SIRT1)는 처음으로 발견된 포유류의 sirtuin이고 일곱개의 알려진 SIRTs (SIRTs 1-7) 가운데 가장 많이 연구된 단백질이다. SIRT1을 활성화 시키는 문질은 노화 관련 질환의 치료에 도움이 될 수 있다는 거으로 알려지고 있다. 그러나, 비록 지금까지 많은 저분자 SIRT1 활성화물질이 보고되었다 할 지라도 새로운 물질의 개발은 SIRT1 생물학적 기능에 대한 이해를 향상시키기 치료학적인 적용을 위하여 계속 요구되고 있디. SIRT1의 효능을 증가시키는 새로운 골격의 화합물을 화합물을 얻기위하여, 우리는 전통 약용 식물자원으로부터 선택적이며 높은 활성을 갖는 화합물에 대한 검색을 실시하였다. In vitroSIRT1 분석법을 사용 하여 약용식물자원을 탐색한 후 두가지 식물자원인 Ailanthus altissima와 Curcuma longa 가 연구를 위한 식물 대상으로 선택되었다. 활성 추적 검색법을 사용하여 12개의 새로운 화합물을 포함한 활성 화합물의 분리하는 성과를 얻었다. 신규 화합물의 목록은 다음과 같다: (2R,3R)-7-(2,3-dihydroxy-3,7-dimethylocta-6-enyloxy)-6,8-dimethoxycoumarin, 6,8-dimethoxy-7-(3,7-dimethylocta-2,6-dienyloxy)coumarin, (2R,3R,6R)-7-(2,3-dihydroxy-6,7-epoxy-3,7-dimethyloctaoxy)-6,8-dimethoxycoumarin, (2R,3R,4S,5S)-6,8-dimethoxy-7-(3,7-dimethyl-4,5-epoxy-2-hydroxyocta-6-enyloxy)coumarin, (3R,4S)-6,8-dimethoxy-7-(3,7-dimethylocta-3,4-epoxy-6-enyloxy)coumarin, (2R,3R,6R)-7-(6,7-dihydroxy-2,3-epoxy-3,7-dimethyloctaoxy)-6,8-dimethoxycoumarin, (3¢R,4¢S)-7-(2¢,3¢:6¢,7¢-diepoxy-6¢-hydroxy-3¢,7¢-dimethyloctaoxy)-6,8-dimethoxycoumarin, (2¢R,3¢R,6¢S)-6,8-dimethoxy-7-(6¢-hydroxy-2¢,3¢-epoxy-3¢,7¢-dimethylocta-7¢-enyloxy)coumarin, (2¢R,3¢R,6¢S)-6,8-dimethoxy-7-(2¢,3¢6¢-trihydroxy-3¢,7¢-dimethylocta-7¢-enyloxy)coumarin (altissimacoumarins C-K), 2-(4,5-dihydroxy-3-methoxyphenyl)methenyl-5-(4-hydroxyphenyl)ethenyl-3(2H)-furanone, 2-(4,5-dihydroxy-3-methoxyphenyl)methenyl-5-(4-hydroxy-3-methoxyphenyl)ethenyl-3(2H)-furanone 과 (1R,3R,5S)-trihydroxy-1-(4,5-dihydroxy-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane (curcuminlongins A-B 와 D). 분리된 신규화합물의 구조분석을 위하여, 1D, 2D-NMR, UV, IR, 및 MS등의 분광학적인 방법과 물리화학적인 기술들이 사용되었다. 본 학위 논문 에서, 모든 신규 화합물의 분리 및 구조 해석등이 시도 되었다. 또한, 화합물의 SIRT1에 대한 작용 및 그들의 구조 - 활성 관계에 대한 연구가 시도되었다. 이러한 결과는 A. altissima와 C. longa로부터 분리된 화합물은 새로운 SIRT1 활성화물질로 가능성을 갖고있어 보다 후속적인 연구가 필요한 것으로 사료 된다.|Silent information regulator two ortholog 1 (SIRT1) was discovered as the first mammalian sirtuin discovered and is the most studied of the seven human sirtuin family members. It has been postulated that activators of SIRT1 might be beneficial in the treatment of aging-associated diseases. However, although some small molecular activators of SIRT1 have been identified recently, new activators are still needed to improve the understanding of SIRT1 biological functions and to discover its possible therapeutic indication. With the hope of gaining promising substances served as lead compounds for stimulating SIRT1 activity, we have focused our efforts on search for highly active compounds isolated from traditional medicinal plants source. After screening thousands of plants by using an in vitro SIRT1 assay, two candidates have been selected for further studies, including Ailanthus altissima and Curcuma longa. Bioactivity guided fractionation of these candidates has resulted in the isolation of a series of substances as active principles, including twelve new compounds: (2R,3R)-7-(2,3-dihydroxy-3,7-dimethylocta-6-enyloxy)-6,8-dimethoxycoumarin, 6,8-dimethoxy-7-(3,7-dimethylocta-2,6-dienyloxy)coumarin, (2R,3R,6R)-7-(2,3-dihydroxy-6,7-epoxy-3,7-dimethyloctaoxy)-6,8-dimethoxycoumarin, (2R,3R,4S,5S)-6,8-dimethoxy-7-(3,7-dimethyl-4,5-epoxy-2-hydroxyocta-6-enyloxy)coumarin, (3R,4S)-6,8-dimethoxy-7-(3,7-dimethylocta-3,4-epoxy-6-enyloxy)coumarin, (2R,3R,6R)-7-(6,7-dihydroxy-2,3-epoxy-3,7-dimethyloctaoxy)-6,8-dimethoxycoumarin, (3¢R,4¢S)-7-(2¢,3¢:6¢,7¢-diepoxy-6¢-hydroxy-3¢,7¢-dimethyloctaoxy)-6,8-dimethoxycoumarin, (2¢R,3¢R,6¢S)-6,8-dimethoxy-7-(6¢-hydroxy-2¢,3¢-epoxy-3¢,7¢-dimethylocta-7¢-enyloxy)coumarin, (2¢R,3¢R,6¢S)-6,8-dimethoxy-7-(2¢,3¢6¢-trihydroxy-3¢,7¢-dimethylocta-7¢-enyloxy)coumarin (altissimacoumarins C-K), 2-(4,5-dihydroxy-3-methoxyphenyl)methenyl-5-(4-hydroxyphenyl)ethenyl-3(2H)-furanone, 2-(4,5-dihydroxy-3-methoxyphenyl)methenyl-5-(4-hydroxy-3-methoxyphenyl)ethenyl-3(2H)-furanone and (1R,3R,5S)-trihydroxy-1-(4,5-dihydroxy-3-methoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)heptane (curcuminlongins A-B and D). Their structures were elucidated on the basic of spectral (including 1D, 2D-NMR, UV, IR, and MS) and physicochemical analyses. Herein, my thesis deals with the isolation, structural elucidation of these compounds. Furthermore, the preliminarily studies on evaluation of stimulating SIRT1 activity of the compounds and their structure-activity relationship are described and discussed. These data suggest that terpenylated coumarins from A. altissima, and curcuminoids from C. longa can be considered as promising classes of SIRT1 activators.