Study On Total Synthesis, Structural Modification, Anti-cancer Activities Of (+)-7-Deoxynimbidiol And Total Synthesis Of 23(Z)-Isofouquierol

Cancer is one of the most significant fatal causes in the world. As a result, the development of new effective anti-cancer compounds is one of the most important destinations of the medicinal and pharmaceutical research. Since the middle of the last century, thanks to the increasingly developing natural product chemistry, a number of new and important naturally occurred anti-cancer drugs such as taxol, colchicine and vincristine have been found, some of these compounds have also been acted as models and lead-compounds of the new drugs for the researches. Therefore, how to obtain more efficacious drugs by synthesizing or modifying the natural products with anti-cancer bioactivities is the highlight in the research of the organic synthesis and pharmaceutical chemistry.The dissertation focuses on the total synthesis, structural modification and investigation of anti-tumor activities of the natural product compounds (+)-7-deoxynimbidiol from the officinal plants Celastrus hypoleucus (Oliv.) Warb, and the total synthesis of 23(Z)-isofouquierol (the skeleton compound of 20(S)-25-tri-hydroxyl-dammar-23(Z)-ene-3-caffeate from Celastrus rosthornianus Loes).1. From the starting materials geranic acid and veratryl aldehyde, the racemic compound (±)-7-deoxynimbidiol and its epimer cis-(±)-7-deoxynimbidiol were obtained (9.2 % yields of eight steps). Four novel aromatic tricycle diterpenes were obtained and their anti-tumor activities against four cultured human-tumor cell lines (Hela, A549, CNE and MCF) were investigated respectively.2. On the basis of the synthesis of (±)-7-deoxynimbidiol, through the chiral separation of the racemic intermediate cyclocitric acid, the natural product (+)-7-deoxynimbidiol, its enantiomer (-)-7-deoxynimbidioland, and their diastereoisomers cis-(+)-7-deoxynimbidiol and cis-(-)-7-deoxynimbidiol were synthesized. Eight novel optically pure aromatic tricycle diterpenes were obtained all together. 3. (±)-7-deoxynimbidiol and cis-(±)-7-deoxynimbidiol were modified in two different approaches to investigate the pharmacophores including etherification of the phenolic hydroxyl with the substituted benzyl bromide and oxidation of the C-6 or C-7. Four series including 34 novel aromatic tricycle diterpenes were obtained. The experiments proved that most of these compounds had anti-tumor activities against four cultured human-tumor cell lines (Hela, A549, CNE and MCF). The results also indicated that the cis- or trans- configurations of the 5-H and 17-CH3 had a great influence on the anti-tumor activities of these compounds against Hela, A549, CNE and MCF, and the compounds with cis- configuration were more active than those with trans- configuration.4. The anti-tumor mechanism of the compound CDN-1 was preliminarily studied. The data from the agarose gel electrophoresis and FCM suggested that, to MCF-7 and SMMC-7721, CDN-1 inhibited the cell proliferation by inducing apotosis of the cells, but to Hela, the phenomenon of apotosis is not obvious. The anti-tumor research in vivo indicated that CDN-1 has the moderate activity against the S180 sarcoma in mice.5. For synthesizing the natural product 20(S)-25-trihydroxyl-dammar-23(Z)-ene-3-caffeate and a series of the dammarane analogues to evaluate the anti-tumor activities of this kind of compounds, the model compound, 23(Z)-isofouquierol, was synthesized via thirteen-step reactions using dammar resin as starting material.