Construction Of The Mother Nucleus Of Elemene-type Compounds And Structural Modification And Bioactivity Of Curcumol Derivatives

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.