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

Yang，Yujian1; Yu，Qiuchun2; Hu，Lean1; Dai，Botao1; Qi，Ruxi4; Chang，Yu2; Zhang，Qingwen5; Zhang，Zhang2; Li，Yingjun1; Zhang，Xumu1,3

2022-12-15

10.1016/j.ejmech.2022.114731

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY   Impact Factor & Quartile

0223-5234

1768-3254

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) 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.

Antineoplastics Asymmetric hydrogenation Cephalotaxine-type alkaloid Enantioselective semisynthesis Homoharringtonine Leukemia

English

First ; Corresponding

Basic and Applied Basic Research Foundation of Guangdong Province[2020A1515110361];National Natural Science Foundation of China[81973158];National Natural Science Foundation of China[82150206];Universidade de Macau[MYRG2019-00150-ICMS];Ministry of Science and Technology of the People's Republic of China[SQ2019YFE010401];Shenzhen Bay Laboratory[SZBL2019062801006];

CHEMISTRY

2-s2.0-85139735965

Scopus

1.Academy for Advanced Interdisciplinary Studies,Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis,Department of Chemistry,and Medi-X Pingshan,Southern University of Science and Technology,Shenzhen,518000,China
2.International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE),Guangzhou City Key Laboratory of Precision Chemical Drug Development,School of Pharmacy,Jinan University,Guangzhou,510632,China
3.Shenzhen Bay Laboratory,Shenzhen,518132,China
4.Cryo-EM Center,Southern University of Science and Technology,Shenzhen,518055,China
5.State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences,University of Macau,999078,Macao

Yang，Yujian,Yu，Qiuchun,Hu，Lean,et al. Enantioselective semisynthesis of novel cephalotaxine esters with potent antineoplastic activities against leukemia[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2022,244.

Yang，Yujian.,Yu，Qiuchun.,Hu，Lean.,Dai，Botao.,Qi，Ruxi.,...&Zhang，Xumu.(2022).Enantioselective semisynthesis of novel cephalotaxine esters with potent antineoplastic activities against leukemia.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,244.

Yang，Yujian,et al."Enantioselective semisynthesis of novel cephalotaxine esters with potent antineoplastic activities against leukemia".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 244(2022).