民间药毛麻楝中新奇结构phragmalin柠檬苦素的发现及其抗炎活性研究

Chukrasia tabularis var. velutina (Wall. ) King is a timber tree of Meliaceae family. Its stem bark has been used traditionally to treatment cold and febrile in China recording in 《Chinese Materia Medica》. Our previous research indicated that the chloroform extraction of its traditional medicinal partion (stem barks) showed significant anti-inflammatory activity, which correspond to its traditional usage. Meanwhile, a series of novel and complex phragmalin-type limonoids with anti-inflammatory activity were isolated from this active partion. The pausible biosynthetic pathway and the structure-function relationship of these isolated limonoids indicated that novel and minor phragmalin-type limonoids but with better anti-inflammatory activity exist in this medicinal plant. Thus, the objective of this project is to discover novel and anti-inflammatory phragmalin-type limonoids from the root barks and fruits of C. tabularis var. velutina based on the integrated skills of quickly find and isolation, structure elucadation, and activity screen bringing up from previous work, and study the base of its anti-inflammatory activity and other activity, and elucidate the active material foundation of its traditional usage finally. On guidance of the traditional usage of C. tabularis var. velutina and modern activity screen, our research is aim to found novel and complex constituens from folk medicinal plant, which is also significant for research & discovery of new drugs with independent intellectual property rights.

毛麻楝为楝科麻楝属植物，《中华本草》记载，毛麻楝的皮入药，性寒味苦，具有疏风清热的功效，用于治疗感冒发热。申请人前期研究发现，民间药毛麻楝传统药用部位茎皮的氯仿萃取部分具有显著的抗炎活性，并从该活性部位中分离鉴定了一系列结构新颖并具有显著抗炎活性的phragmalin柠檬苦素衍生物。前期的生物合成途径研究和抗炎活性筛选结果预示着该属植物中仍存在微量的、结构新颖的、抗炎活性显著的phragmalin柠檬苦素衍生物。本项目拟在前期工作基础上，从研究较少的毛麻楝根皮和果实中定向寻找和分离鉴定结构新颖的phragmalin柠檬苦素，并深入研究抗炎活性机理和其他生物活性，进一步阐明毛麻楝的药效物质基础。本项目依据毛麻楝的传统功效，并在现代药理活性研究的指导下，从民间药物中发现结构新颖的活性成分，这对具有自主产权新药的研究与开发也具有重要的意义。

在本项目的前期研究中,从用于治疗感冒发热的民间药物毛麻楝中分离鉴定了一系列结构新颖并具有显著抗炎活性的phragmalin柠檬苦素衍生物。因此本项目拟在前期研究基础上，继续从毛麻楝及其近缘植物麻楝中定向寻找和分离鉴定结构新颖的phragmalin 柠檬苦素，并深入研究该类化合物的生物活性，为该类化合物的进一步研究开发奠定基础。在本项目的研究中，首先总结了前期分离得到的phragmalin柠檬苦素的结构与紫外光谱的关系、单体phragmalin柠檬苦素的质谱裂解规律，建立了UPLC-DAD-Q-TOF/MS在线识别Phragmalin柠檬苦素的方法。在以上规律和方法的指导下，从毛麻楝前期研究的剩余浸膏中识别并分离新的phragmalin柠檬苦素化合物8个；从麻楝种子中定向发现并分离鉴定16个结构新颖的C-15烯醇式酰基phragmalin柠檬苦素原酸酯，其中8个为首次报道的C-15乙酰基phragmalin柠檬苦素原酸酯。对所分离化合物的生物合性筛选显示， C-15乙酰基phragmalin柠檬苦素具有显著的抗炎活性以及逆转肿瘤细胞多药耐药活性，初步的研究还发现该类化合物具有显著的HSP90抑制活性。综上所述，本项目从毛麻楝及其近缘植物中共分离坚定24个新的phragmalin型柠檬苦素，其中8个为首次报道的C-15烯醇式乙酰基phragmalin柠檬苦素原酸酯，同时进一步扩大了phragmalin柠檬苦素的生物活性研究范围，为该类来自于楝科的天然产物的进一步开发利用奠定了基础。