| The work of this thesis is divided into two parts:1.Design,synthesis and preliminary biological activity evaluation of the dual-target memantine derivatives with histone deacetylases(HDACs)inhibitors as the skeleton structure.2.Improved synthesis of Chidamide and the design,synthesis and preliminary biological activity evaluation of its derivatives.Many recent studies have shown that epigenetic modifications play an important role in neurodegenerative diseases,and HDACs are important regulatory roles in the cognitively relevant gene expression and signal transduction of in patients with Alzheimer’s disease(AD),which providing a new drug target for the treatment and research of AD.However,the specific roles and neuroprotective or neurotoxic effects of different subtypes of HDACs in the cognitive function changes of AD are all different,while the important roles of HDAC2 and HDAC6 in the occurrence and development of AD have been studied most widely.In addition,the broad application of HDACs in the field of tumor therapy is also limited by its large side effects.Therefore,the study of HDACs subtype selective inhibitors is of great significance in the field of AD and tumor therapy.However,for complex diseases such as AD and tumors,drugs that target a single target often do not produce a good therapeutic effect on such diseases.The multi-targeted drugs simultaneously intervene multiple targets and multiple nodal proteins of a complex disease mechanism network,and modulate the entire disease mechanism network,will be a superior therapeutic strategy.Memantine hydrochloride is the only N-methyl-D-aspartate receptor(NMDAR)antagonist marketed for the treatment of AD,which is the only anti-AD drug marketed in the past 15 years.Our group designed 32 novel memantine derivatives of HDACs-NMDAR dual target anti-AD based on the pharmacophore model of HDACs inhibitors.We adopted the chemical structure of memantine as a Cap group,different types of fatty and aromatic chains are used as linkers,and hydroxamic acid,benzamide or oxime groups are used as ZBGs.After preliminary in vitro activity evaluation,we found compound 9d showed NMDAR-HDAC dual-target inhibitory activity,and mildly selectively inhibit HDAC6,while it also maintained NMDAR antagonistic activity comparable to memantine,both of the IC50 are at the same level.Compound 9d also showed strong neuroprotective to H2O2 injured PC 12 cells(30 times of Trolox),and also exhibited excellent blood brain barrier penetration,which can be used as a potential anti-AD dual-target drug.In addition,we also screened out hydroxamic acid compound 12b and benzamide compound 13b with good inhibitory activities to HDACs,both of which showed high antitumor cells proliferation activities.We have not only designed and screened out highly active compounds against AD or tumors,we have also demonstrated it as a more efficient drug research direction about anti AD or tumors.In addition,we also conducted research on the process optimization and derivatives of the anti-cancer drug Chidamide,which has proprietary intellectual property rights in China.There are few researches on the improved synthesis of Chidamide all over the world,and the existing synthesis processes still have a large optimization space.The total yield increased from 29%of the original process to 47%after optimization,and the reaction time has been greatly shortened which has reduced the production costs.To further explore candidate drugs with higher selectivity and lower side effects and further elucidate the structure-activity relationships of Chidamide,this study started with the SAR of benzamide HDACs inhibitors by introducing different aromatic substituents to the para position of Chidamide’s free amino group.The 14 A cavity in the HDACs active pocket can be occupied by aromatic substituents which will obtain novel derivatives with higher selectivity and inhibitory activity.Based on this,12 novel derivatives of Chidamide have been designed and synthesized,and the derivatives are not within the scope of patent protection.However,during the evaluation of in vitro HDACs inhibitory activities and in vitro anti-tumor cells proliferation activities,all derivatives exhibited worse HDACs inhibitory activity and anti-tumor activity compared to Chidamide. |
