Design, Synthesis And Antitumor, Neuroprotection Activity Of Podocarpane Tricyclic Diterpene Analogues

Tricyclic diterpenoids are exhibiting a wide range of biological activities, which were obtained from the natural products. However, the scarcity and poor activities of these compounds frequently limit their developments. Therefore the seeking of modified natural-based compounds and synthetic natural analogs are effective strategies in drug discovery.To improve antitumor activity, a series of novel tricyclic diterpene derivatives were synthesized based on lead compound A. Compound A was discovered by screening a small synthetic natural product-like (NPL) library. Compounds B-7 and B-9 exhibited high potency antitumor activity (the average IC50=0.357μM and 0.294 μM) which were 12.9 and 15.6 folds more potent than compound A, and displayed less toxic on human fibroblasts (HAF) in comparison with the tumor cell lines. In further SAR researches, cyano enone group was introduced to ring A of these diterpenoids derivatives. To our delight, these promising cyano enone compounds possessed high potency antitumor activity on multidrug resistance cell line MCF-7/ADR.To improve neuroprotection activity, a series of tricyclic diterpene derivatives were synthesized based on the lead compound 6, and their neuroprotective effects were further evaluated against glutamate-, oxygen and glucose deprivation(OGD)-and nutrient deprivation-induced neuronal injury using cell-based assays. To our delight, most of these synthetic compounds exhibited increased neuroprotective effects and blood-brain barrier (BBB) permeability without cellular toxicity. The most potent compound E-5, showed significantly improved neuroprotection against neuronal injury in primary neurons. Furthermore, compound E-5 exhibited remarkable neuroprotection in transient middle cerebral artery occlusion (tMCAO) rats by reducing their infarct sizes and neurological deficit scores. A mechanistic exploration using in vitro and in vivo experiments showed that the neuroprotection of compound E-5 was at least partly mediated by improving the levels of glutathione (GSH), superoxide dismutase (SOD) and heme oxygenase-1 (HO-1) protein. Therefore, these diterpene derivatives could be used as promising leads for the development of a new type of neuroprotective agents.In conclusion, this paper provides high quality lead compounds for the development of antitumor and neuroprotective drugs.