Design, Synthesis And Activity Evaluation Of Novel Cdk5 Inhibitors

Alzheimer's disease (AD), a degenerative disease of the central nervous system, was one of the most common senile dementia. Dysfunction of cylin-dependent kinase 5 in phosphorylation of Tau protein,β-App, NF-M and NF-H has closely implicated in Alzheimer's disease.Recently, cylin-dependent kinase-5 was a novel therapeutic target of Alzheimer'disease, and inhibitors targeting Cdk5 might be a new breakthrough for AD therapy.Mainly research aspects and results:1 Construction of pharmacophore model of Cdk5 and target compounds designMaking use of computer aided drug design software—Catalyst, a pharmacophore model of Cdk5 was constructed. Selecting the indolone as a fundamental structure and restructuring the 1,3 sites of indolone, a series of compounds which matched well with the pharmacophore model of Cdk5 were design. Drug-like analysis of these compounds and activity prediction basing on this pharmacophore model were carried out.2 Synthesis of target compounds and their structures identificationRestructuring the 1,3 sites of indolone, we synthesized 12 new compounds by ordinary chemistry experiment. Convenient synthetic procedures, simple synthetic conditions and high productive rates were the feature of whole synthesis process. Purity analysis of all compounds was carried out by HPLC, and structure identification was operated by UV, IR, ¹H-NMR, 13C-NMR. What's more, we found that all compounds had tautomerism (Z/E) when dissolved in different solvent system. 3 Pharmacological activity test in vitroThe initial neuroprotective effect in vitro: the apoptosis model of neural cells, which was induced by the oxidative substance, was constructed by H₂O₂ acting on SH-SY5Y cell. The survival rate of cell was assessed by MTT methods, and was used to check the ability of all target compounds to protect SH-SY5Y cells against H₂O₂ inducing SH-SY5Y cells apoptosis. The results indicated that 1,3-disubstituted indolones had obvious neuroprotective effect. Pharmacological activity experiment also indicated that Comp2, Comp3, Comp7 had high activity in protecting SH-SY5Y cells against H₂O₂ inducing SH-SY5Y cells apoptosis, and Comp4, Comp6, Comp8, Comp9 also had some neuroprotective effect.4 Discussion(the feature and innovation of this research)1. A pharmacophore model of Cdk5 was constructed, and it would be a guidance for rational design of Cdk5 inhibitors.2. Selecting the indolone as parent structure and restructuring its 1,3 sites, I synthesized 12 novel compounds by simple and convenient synthetic methods. It would be a new way for designing and synthesizing Cdk5 inhibitors.3. It was the first time to discover that derivatives of indolones had the effect of inhibiting SH-SY5Y cell apoptosis induced by H₂O₂.