| Alzheimer's disease (AD) is the most common disease occurred in aged people worldwide. The mail clinical symptom is progressive cognitive decline and mental deterioration. AD is neuropathologically characterized by senile plaque composed by amyloid protein, neurofibrillary tangle depositions, basal forebrain cholinergic deficit, and extensive neuronal loss and synaptic changes in the cortex and hippocampus. According to the cholinergic deficiency hypothesis of AD, one of therapeutic methods is the employment of acetylcholinesterase (AChE) inhibitors which act through inhibiting the hydrolysis of acetylcholine.Territrem B (TRB) shows potent inhibitory activity against AChE with IC50 value of 7.8 nmol·L-1 which was first isolated from the culture broth of Aspergillus terreus by Chinese scientists in 1979. Furthermore, its inhibitory mechanism is different from the AChE inhibitors which were licensed by FDA for therapy of AD. Its hypotoxicity and high selectivity against AChE make TR B become the ideal lead compound in developing new AChE inhibitors.Up to now, extensive structure-activity relationship (SAR) investigations of TRB have not been researched. Simplification on the A/B ring system should allow one to produce adequate amounts of derivatives that can be subjected to SAR studies under different aspects. Accordingly, one types of parent compounds 2.8 were designed and synthesized, in which N-atom was introduced. Then O- atoms substituted N-atom for preparation parent compounds 2.9 on account of isostere principle. When analysis the structures of TRB and its analogs, it is evident that the electron-poor enone A-ring was attached with the pyranone D-ring by a three-bond-linker. In order to compare the inhibitive effects of different substitute methoxy groups in benzene ring, another type compounds 2.10 were designed and synthesized. Moreover, parent compound 2.11 was designed by changing hybridization of carbon which attached with the pyranone D-ring at 7-position. Compounds 2.13 were synthesized to study the relation between unplane structure of D/E ring and the inhibitive effects upon AChE.Total one hundred compounds were designed and synthesized. Among them,eighty seven compounds have not been reported yet. Then AChE inhibitory activities and cytotoxicities towards six different human tumor cell lines of partial target compounds were evaluated and primary SAR were analysed. The structures of the target compounds were confirmed by 'HI NMR , ESI-MS and IR.This thesis includes five chapters altogether. The first is preface and the following chapter describes the standpoints on designing series of new target compounds. The preparations of designed compounds were recounted in chapter three. The AChE inhibitory activity as well as the cytotoxic activity of some target compounds were evaluated and further analysed in chapter four. Chapter five is review introducing the present situation of AD therapeutic development and AChE inhibitors studying development in latest years.According to the biological activity results, compounds 3.9.5, 3.9.16, 3.9.17, 3.9.18 exhibited significant inhibition activities to AChE with IC50 values at 9.1 x lO"5 mol-L"1, 8.6 x lO"5 mol-L'1, 16.0 x lO"5 mol-L"1, 7.2 x lO"5 mol-L"1,respectively. These three compounds were less cytotoxic except 3.9.18. These results raise the possibility of using TRB anologues as a novel therapeutic approach for the treatment of AD.
|
PDF Full Text Request