Synthesis And Biological Evaluation Of Diversified Hamigeran B Analogs And Cyathane Intermediates

Neurodegenerative diseases,such as Parkinson's disease?PD?and Alzheimer's disease?AD?,affect millions of people worldwide.In general,neuronal differentiation involves the growth,elongation,and bifurcation of neuronal branches out of the neuronal cell body,and this process is essential for the maintenance of the nervous system.Neurodegenerative diseases occur when cells in the brain or peripheral nervous system lose function over time and ultimately die.The molecules collectively referred to as neurotrophins that promote the survival,maintenance,and regeneration of neuronal populations can be used as a remedy against neurodegenerative diseases.Nerve growth factor?NGF?,brain-derived neurotrophic factor?BDNF?,neurotrophins like NT-3,NT-4,NT-5,have attracted attention as potential therapeutics for severe neurodegenerative diseases such as AD or as regeneration-promoting compounds.However,their protein properties such as complex structures and high molecular weight eliminated them for using as clinical medication.Hence,the search for small molecules with the NGF biological functions or the NGF-induced neurotrophic activity arouses high interest.Cyathanediterpenes are widely distributed in nature,with huge Numbers,complicated scaffold and diverse biological activities.The Hamigeran diterpenoids,which are structurally analogical to cyathanes,also known as the burgeoning marine-derived natural products.They all have ABC tricarbocyclic ring system,multiple stereogenic centers,and are punctuated by carbons at a variety of oxidation states.This dissertation mainly focuses on the diterpenes,namely Cyathanes and Hamigerans.1.This article reports a synthetic plan of bicyclo[5/6]key intermediate of cyathane.All the involved reactions,such as nucleophilic substitution reaction,radical ring-closing reaction,Johnson-Claisen rearrangement and Grignard addition,were optimized for higher yields.The procedure provides a simple and efficient method for the synthesis of bicyclo-key intermediate of cyathane.It is expected to have wide applications in the synthesis of cyathane.2.We have enantioselectively synthesized for the first time Hamigeran Bskeleton analogs with high yield,structurally related to cyathane diterpenoid scaffold.This methodology provides a route for the rapid assemblyof the hamigeran pool in a practical fashion and sufficient quantities to facilitate drug discovery.Then we describe the efficient synthesis of a series of new simplified hamigeran B and 1-hydroxy-9-epi-hamigeran B norditerpenoid analogs?23 new members in all?.3.We describe anti-neuroinflammatory and neurite outgrowth-stimulating?neurotrophic?activity of Cyathane intermediatesand Hamigeran B analogs.All compounds exhibited moderate nerve growth factor?NGF?-mediated neurite-outgrowth promoting effects in PC-12cells at the concentration of 20?M.Amongthem,the Preliminary anti-neuroinflammatory studyof dicyclic[5/6]Cyathane intermediates showedremarkable effect,which is valuable for further study in more depth.Compounds 3-6b,3-6c,3-6o,3-6q,and 3-6t showed significant nitric oxide?NO?production inhibition in lipopolysaccharide LPS-activated BV-2 microglial cells,of which 3-6c and 3-6q were the most potent inhibitors,with IC₅₀ values of 5.85 and6.31?M,respectively.Two derivatives 3-6q and 3-6o as bifunctional agents displayed good activities as NO production inhibitors and neurite outgrowth-inducers.Cytotoxicity experiments,H₂O₂-induced oxidative injury assay,and ELISA reaction speculated that compounds may inhibit the TNF-?pathway to achieve anti-inflammatory effects on nerve cells.Moreover,molecular docking studies provided a better understanding of the key structural features affecting the anti-neuroinflammatory activity and displayed significant binding interactions of some derivatives?like 3-6c,3-6q?with the active site of i NOS protein.These results demonstrated that this structural class compounds offered an opportunity for the development of a new class of NO inhibitors and NGF-like promotors.