【作者】 梁大伟；

【导师】 董金华；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2014， 博士

【摘要】 温莪术挥发油具有抗癌、抗病毒等多方面生物活性。过去的研究发现其中的榄香烯、莪术醇、莪术二酮等倍半萜类化合物为其主要活性成分。本论文针对榄香烯型分子骨架的构建和莪术醇的结构修饰及活性进行了研究。第一部分：榄香烯型萜类分子中1,2-二烯基环己烷母核骨架的构建及合成研究榄香烯型萜类化合物在自然界中广泛的存在,具有抗癌、抗炎、抗病毒等多种重要生物活性。在化学结构上,此类萜类天然产物分子普遍含有顺式或者反式1,2-二烯基环己烷母核骨架,类似于(±)-geijerone。本文以构建1,2-二烯基环己烷母核结构骨架为目的,并应用于(±)-geijerone的合成研究中,作为研究合成榄香烯型萜类分子的一部分。设计采用易得的geraniol为起始原料,运用Ireland-Claisen重排策略构建顺式和反式1,2-二烯基结构片断,并以分子内Barier反应环合作为关键反应步骤,进行了13步易于操作的反应步骤合成(±)-geijerone及(±)-5-epi-geijetone。本文丰富了1,2-二烯基环己烷结构片断及(±)-geijerone的合成方法,同时为研究合成榄香烯型化合物提供有价值的指导。第二部分：萜类分子莪术醇的结构修饰及生物活性研究萜类分子莪术醇是中药莪术的有效成分之一,其具有广泛的抗病毒、抗肿瘤、抗炎等活性,具有潜在的临床应用开发价值。目前,对于莪术醇的结构修饰及相应的生物活性研究的报道较少。本部分根据莪术醇的结构特点,通过化学方法对其结构的不同部位进行改造研究,合成了27个莪术醇衍生物,其中24个为未见报道的新化合物。采用MTT法对这些化合物进行初步体外抗肿瘤(细胞HeLa,HepG2,HT-1080,HCT116,A375-S2,MCF-7,A549,U-937, K562与HL60)活性筛选,结果发现卓酮化合物197对细胞HepG2与HCT116的抑制活性增强,分别为23.61与21.01μM；C7位引入羟基的ESC-01及环外双键末端引入亲水性的氨基硫脲片断的ESC-03对细胞HCT116的抑制活性增强,分别为22.42与16.35μM；桥环半缩醛还原开环化合物ESC-07对细胞A375-S2、细胞HT-1080的抑制活性增强,分别为34.45与32.71μM；6位羟基与α、β-不饱和肉桂酸系列成酯衍生化化合物ESC-09～ESC-23没有表现出明显的活性改善,且无明显的构效关系。其中,肉桂酸苯环上无取代基的ESC-09对细胞HL60的抑制活性提高明显,为10.46μM。此外,苯环上无取代基的ESC-09、对位为甲氧基取代的ESC-11、芳环为噻吩的ESC-22分别对细胞HT-1080、HL60、HCT116的抑制活性提高。而6位羟基与p-卤代酰胺成醚衍生物ESC-24与ESC-26对人肝癌细胞HepG2的抑制活性提高明显,分别为9.85与6.17μM。本部分不仅考察了莪术醇结构在不用化学环境体系下的稳定性,加深了对其结构特点的认识,而且可以通过体外抗肿瘤活性结果为我们进一步优化莪术醇的结构,开发具有临床应用价值的莪术醇类似物提供指引。更多还原

【Abstract】 The essential oil extraced from Rhizoma Curcuma contains elemenes, curcumol, curdione and other sesquiterpenes has been reported to have many different biological activities, such as anti-cancer, anti-virus. This thesis aims to make a research on the construction of the mother nucleus of the elemene-type terpenoids and structural modification and bioactivity of curcumol derivatives:1. Synthetic studies on the construction of the1,2-dialkenylcyclohexane framework of the elemene-type terpenoids.The elemene-type terpenoids are widely existed in various natural products. These compounds or their racemic mixtures have been shown to inhibit tumor cell growth, anti-inflammatory and anti-virus in vitro and in vivo. Structurally, they contain a highly functionalized syn-or anti-1,2-dialkenylcyclohexane skeleton, which was similar to the strcuture of (±)-geijerone. Therefore,(±)-geijerone could be considered as a common precursor in the synthesis of elemene-type terpenoids. Here, we present a13-step for the synthesis of (±)-geijerone and a diastereoisomeric mixture with its5-epimer, which starting from the commercially available geraniol. Construction of the syn-and anti-1,2-dialkenylcyclohexane skeleton was achieved via Ireland-Claisen rearrangement of the (E)-allylic ester, and the cyclohexanone moiety was derived from the iodoaldehyde via intramolecular Barbier reaction. The newly formed syn-and anti-1,2-dialkenylcyclohexane strategy not only enrichs the synthetic methods of syn-and anti-1,2-dialkenylcyclohexane framework and (±)-geijerone, but also allows rapid access to various epimers and analogues of elemene-type products.2. Structural modification and bioactivity of curcumol derivativesCurcumol is an active ingredient of curcuma, a traditional Chinese medicine. It has present many important bioactivities, such as anti-virus, anti-tumor, anti-inflammatory and so on. At the present, the reports of the structural modification and bioactivity of curcumol are relatively rare. Here, on the base of the structural features, twenty-seven derivatives were synthesieed by modification of several active sites of curcumol. And the preliminary evaluation of these derivatives in vitro anti-tumor activity is screened using an MTT assay with HeLa, HepG2, HT-1080, HCT116, A375-S2, MCF-7, A549, U-937, K562and HL60. The results show that the IC50values of compound197, ESC-01, ESC-03, ESC-22for HCT116cells were21.01,22.42,16.35and21.51pM, which is stronger than curcumol. The IC50values of compound197, ESC-24, ESC-26for HepG2cells were23.61,9.85and6.17and the IC50values of compound ESC-07and ESC-09for HT-1080cells were32.71and27.71respectively. They are all stronger than curcumol. In addition, The IC50values of compound ESC-09and ESC-11for HL60cells were10.46and20.29μM, respectively, about five times stronger than curcumol. The structural modification of C6, C7and C8position and the decomposition of hemiacetal’s bridge of curcumol was not effectively improve the inhibitory activities of tumor cells in vitro, and has no clear structure-activity relationship of curcumol derivatives. These not only investgate the stablization of curcumol in different chemical environments to deepen understanding of its structural characteristics, but also give us a guidance to exploit valuable curcumol derivatives in clinic according to the results of anti-tumor activity.更多还原