Plinabulin is a synthesized diketopiperazine type tubulin inhibitor discovered based on the structure-activity relationship（SAR）study of Phenylahistin, which was isolated from Aspergillus. It was observed that Plinabulin binds between alpha and beta tubulin subunit which is close to colchicine-binding site of tubulin. Further study indicated that it has good efficacy, pharmacokinetics and safety properties, current it is in phase III clinical study. Now, we are working on optimization of its synthesis process. With ethyl isocyanoacetate and three methyl acetic anhydride as starting materials, the imidazole aldehyde was obtained through four steps; and then the target molecule was accomplished through two steps of condensation reaction, the total synthesis yield is 12%. The double bond Z, E isomers can be produced in the second condensation reaction, and the Z isomer, which has anti-tumor activity, can be obtained by avoiding light. Bioactivity screening indicated that Plinabulin has strong inhibition the growth of A431 human skin cancer cell, the inhibition rate was 91.8% in 12.5 nm concentration conditions. The intracellular fluorescence intensity of the microtubule protein enhanced, and the cell morphology altered were observed with using Alexa488 staining. In order to obtain a new generation of anti-tumor drugs with better biological activity and to overcome the existing drug resistance, our group has designed and synthesized a series of novel derivatives based on the structure of Plinabulin. MBRI-001, a new marine anti-tumor drug candidate having good druggability, was selected to preclinical study through activity screening, preliminary pharmacokinetics and safety studies. Key words: Plinabulin；Tubulin inhibitor；Marine drug; Anti-tumor drug candidate Reference： [1] Yamazaki, Y.; Hayashi, Y.; et al. J. Med. Chem. 2012, 55, 1056−1071.

Plinabulin: A marine drug candidate for anti-tumor

251st National Meeting (2016)

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