Synthesis and pharmacokinetic property improvement of deuterated plinabulin 9 |
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| Authors: | Jianchun Zhao Hejuan Cheng Tianwen Sun Shixiao Wang Zhongpeng Ding Guifang Dou Zhiyun Meng Huashi Guan Wenbao Li |
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| Institution: | 1.Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy,Ocean University of China,Qingdao,P. R. China;2.Marine Biomedical Research Institute of Qingdao,Qingdao,P. R. China;3.Institute of Transfusion Medicine,Academy of Military Medical Science,Beijing,P. R. China |
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| Abstract: | Plinabulin, a potent microtubule-targeting agent, is derived from marine natural diketopiperazine ‘phenylahistin’. To develop novel plinabulin analogue that could display better pharmacokinetic properties and less side effects, deuterated plinabulin 9 was synthesized and evaluated in vitro and in vivo. In comparison with plinabulin, in vivo pharmacokinetic studies indicated that the deuterated derivative 9 could alter blood circulation behavior obviously, which was proved by increased area under the plasma concentration- time curve (AUC0–∞), reduced clearance (CL), and prolonged total body mean residence time (MRT). The derivative 9 also has higher inhibition rates against BxPC-3, Jurkat and A-431 tumor cell lines as compared with its prototype plinabulin. Therefore, the deuterated compound 9 might be developed as a potential agent for different cancer treatments. |
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