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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

[ Vol. 14 , Issue. 5 ]

Author(s):

Yue Zhong, Yu-Ting Lu, Ying Sun, Nian-Guang Li, Ting Gu, Wen-Yu Wu, Shao-Peng Yu and Zhi-Hao Shi*   Pages 478 - 484 ( 7 )

Abstract:


Background: Discovery of novel agents with anticoagulant and antioxidant activity is very important to treat cerebrovascular disease. Lead compound LR3d discovered in our laboratory exhibited 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 and antioxidant activity.

Methods: By utilizing a scaffold hopping strategy on LR3d, we describe the design and synthesis of a series of novel hexacyclic scutellarein derivatives 4 with a 1,3-oxazine ring fused at positions 7 and 8 in A ring. The thrombin inhibitory activities of all these new compounds were studied by the analysis of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). The antioxidant abilities of these analogs were evaluated by using 3-(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 were synthesized, the results of the biological activity evaluation showed that compound 4e exhibited stronger anticoagulant and antioxidant ability compared to LR3d.

Conclusion: 4e could be used for further development to treat ischemic cerebrovascular disease.

Keywords:

Ischemic cerebrovascular disease, thrombin, antioxidant, scutellarin, scutellarein, scaffold hopping, 1, 3-oxazine.

Affiliation:

Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, Department of Organic Chemistry, China Pharmaceutical University, Nanjing, Jiangsu 211198

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