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Enantioselective semisynthesis of novel cephalotaxine esters with potent antineoplastic activities against leukemia

Cephalotaxine-type alkaloids (CTAs), represented by homoharringtonine (HHT, 1), display potent efficacy against different types of leukemia cells. In this study, a method for hydrogenation of β-substituted itaconic acid monoesters with chiral Ru[DTBM-SegPhos](OAc)2 was developed. This metal-catalyze...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2022-12, Vol.244, p.114731-114731, Article 114731
Main Authors: Yang, Yujian, Yu, Qiuchun, Hu, Lean, Dai, Botao, Qi, Ruxi, Chang, Yu, Zhang, Qingwen, Zhang, Zhang, Li, Yingjun, Zhang, Xumu
Format: Article
Language:English
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Summary:Cephalotaxine-type alkaloids (CTAs), represented by homoharringtonine (HHT, 1), display potent efficacy against different types of leukemia cells. In this study, a method for hydrogenation of β-substituted itaconic acid monoesters with chiral Ru[DTBM-SegPhos](OAc)2 was developed. This metal-catalyzed asymmetric hydrogenation enabled the convenient semisynthesis of novel cephalotaxine derivatives with chiral 2′-substituted-succinic acid 4-mono-methyl esters as side chains. The preliminary structure-activity relationship (SAR) of the compounds' antineoplastic activities was studied. Eventually, we discovered compound 10b with potent antineoplastic activities against leukemia and broadly anticancer activities against a panel of cancer cells. Our study provided a highly enantioselective process enabling the semisynthesis of cephalotaxine derivatives, which are interesting for further study on a scientific basis. [Display omitted] •Novel cephalotaxine derivatives were designed and semi-synthesized.•Asymmetric hydrogenation of β-substituted itaconic acid was developed as a key step.•10b exhibited broad anti-leukemia activity and reduced the expression of oncoproteins.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2022.114731