title: Development of MBRI-001, a deuterium-substituted plinabulin derivative as a potent anti-cancer agent.
abstract: Plinabulin, a drug targeting microtubule of cancer cells, has been currently tried in its phase III clinical study. However, low efficacy caused by poor pharmacokinetic (PK) properties has been considered to be the main obstacle to approved by the Food and Drug Administration. Herein, we introduced a deuterium atom as an isostere in its structure to become a new compound named (MBRI-001, No. 9 in a series of deuterium-substituted compounds). The structure of MBRI-001 was characterized by HRMS, NMR, IR and a single crystal analysis. MBRI-001 exhibited better pharmacokinetic characteristics than that of plinabulin. Additionally, its antitumor activity is in a low nanomolar level for a variety of cancer cell lines and high activity against human NCI-H460 xenograted in mice intravenous administration. Importantly, continuous administration of MBRI-001 exhibited lower toxicity compared to docetaxel. We thus suggest that MBRI-001 could be developed as a promising anti-cancer agent in near future.
authors.affiliation: Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.
authors.forename: Zhongpeng
authors.initials: Z
authors.lastname: Ding
authors.affiliation: Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China.
authors.forename: Hejuan
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Marine Biomedical Research Institute of Qingdao, Qingdao 266071, People's Republic of China.
authors.forename: Shixiao
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, People's Republic of China.
authors.forename: Yingwei
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, People's Republic of China.
authors.forename: Jianchun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, People's Republic of China.
authors.forename: Huashi
authors.initials: H
authors.lastname: Guan
authors.affiliation: Key Laboratory of Marine Drugs of Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, People's Republic of China; Marine Biomedical Research Institute of Qingdao, Qingdao 266071, People's Republic of China. Electronic address: wbli92128@ouc.edu.cn.
authors.forename: Wenbao
authors.initials: W
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D002460:Cell Line; D003903:Deuterium / Q000737:chemistry*; D054659:Diketopiperazines / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054659:Diketopiperazines; C514351:NPI 2358; D003903:Deuterium
keywords: Deuterium substituted; Docetaxel; Microtubule; Pharmacokinetic properties; Plinabulin