Scaffold Hopping Strategy for the Design, Synthesis and Biological Activity Evaluation of Novel Hexacyclic Scutellarein Derivatives with a 1,3-Oxazine Ring Fused at A-ring

摘要

Background: Discovery of novel agents with anticoagulant and antioxidant activity isvery important to treat cerebrovascular disease. Lead compound LR3d discovered in our laboratoryexhibited stronger anticoagulant ability and good antioxidant activity, compared with scutellarein(2), which is the major in vivo active metabolite of the natural product scutellarin (1).Objective: Design and synthesis novel scutellarein derivatives with improved anticoagulant andantioxidant activity.Methods: By utilizing a scaffold hopping strategy on LR3d, we describe the design and synthesisof a series of novel hexacyclic scutellarein derivatives 4 with a 1,3-oxazine ring fused at positions7 and 8 in A ring. The thrombin inhibitory activities of all these new compounds were studied bythe analysis of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombintime (PT) and fibrinogen (FIB). The antioxidant abilities of these analogs were evaluated by using3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method through 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay.Results: Nine new hexacyclic scutellarein derivatives with a 1,3-oxazine ring fused at A-ring weresynthesized, the results of the biological activity evaluation showed that compound 4e exhibitedstronger anticoagulant and antioxidant ability compared to LR3d.Conclusion: 4e could be used for further development to treat ischemic cerebrovascular disease.