Design, Synthesis And Biological Evaluation Of Tricyclic Diterpene Analogues

Natural tricyclic diterpenoids have demonstrated a variety of biological activities. However, the extraction of tricyclic diterpenoids from plants has proven to be inefficient and synthetic routes existing are also inefficient by now. We applied an efficient method to synthesize tricyclic diterpene analogues with structure diversities and expected to obtain lead compounds of anti-osteoporosis and anti-microbial by biological evaluation.Tricyclic diterpene analogue11was synthesized by coupling reaction under Li2CuCl4and then cyclization reaction under MeAlCl2. Through biological evaluation of the compound library derivated from compound11, we found compound37having anti-osteoporosis activity (IC50=5μM) and compound30having anti-microbial activity (Newman strains, MIC=4-5μg/mL).To improve anti-osteoporosis activity, a series of derivates of compound37were synthesized. The C3hydroxyl modified derivates showed weaker inhibitory effect than compound37. We also synthesized a series of esters of compound37, in which, compound C-1showed more potent inhibitory effect (ICso=2μM) than37. Introducing long chain and big ester or amide groups on the benzene ring of37would result in cytotoxicity.To improve anti-microbial activity, a series of derivates based on compound30were synthesized. The pyrazole modified derivates showed weaker anti-microbial activity than compound30. The analogues by introduction of short alkyl chains or halogen on the benzene ring showed improving anti-microbial activity significantly, especially compound E-3and E-8showed strong inhibitory effects against antibiotic resistant S. aureus NRS-1、NRS-271、NRS-70、NRS-100、NRS-108, with MICs of 1.56-3.12.3.12-6.25.0.7-1.56.1.56-3.12.1.56-3.12μg/mL and1.56-3.12.1.56-3.12.1.56-3.12.1.56-3.12.1.56-3.12μg/mL, respectively.In conclusion, this thesis provides new ideas for the development of anti-osteoporosis and anti-microbial drugs.