Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA

Cheng, Min-Jing1,2,3; Wu, Yan-Yi1,2,3; Zeng, Hao4; Zhang, Tian-Hong1,2,3; Hu, Yan-Xia1,2,3; Liu, Shi-Yi5,6; Cui, Rui-Qin5,6; Hu, Chun-Xia5,6; Zou, Quan-Ming4; Li, Chuang-Chuang7; Ye, Wen-Cai1,2,3; Huang, Wei5,6; Wang, Lei1,2,3

2024-07-13

10.1038/s41467-024-49629-8

NATURE COMMUNICATIONS   影响因子和分区

2041-1723

["The development of new antibiotics continues to pose challenges, particularly considering the growing threat of multidrug-resistant Staphylococcus aureus. Structurally diverse natural products provide a promising source of antibiotics. Herein, we outline a concise approach for the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners. The strategy involves rapid assembly of the challenging benzopyrano[2,3-a]xanthene core, highly diastereoselective establishment of three contiguous stereocenters through a retro-hemiketalization/double Michael cascade reaction, and a Mitsunobu-mediated chiral resolution approach with high optical purity and broad substrate scope. Quantum mechanical calculations provide insight into stereoselective construction mechanism of the three contiguous stereocenters. Additionally, this work leads to the discovery of an antibacterial agent against both drug-sensitive and drug-resistant S. aureus. This compound operates through a unique mechanism that promotes bacterial autolysis by activating the two-component sensory histidine kinase WalK. Our research holds potential for future antibacterial drug development.","Structurally diverse natural products are a promising source of antibiotics. Here, the authors report the collective asymmetric total synthesis of polycyclic xanthene myrtucommulone D and five related congeners and discover a compound active against both drug-sensitive and drug-resistant Staphylococcus aureus."]

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英语

通讯

National Natural Science Foundation of China (National Science Foundation of China)["82104019","82373750","82173859","82293681","82293680"] ; National Natural Science Foundation of China[2022YFE0205500] ; National Key R&D Program of China[2024B1515040014] ; Guangdong Basic and Applied Basic Research Foundation[2020B1111110004] ; Key-Area Research and Development Program of Guangdong Province[202102070001] ; Science and Technology Projects in Guangzhou[2021M691260] ; China Postdoctoral Science Foundation[KJZD20230923115116032]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001266864200003

NATURE PORTFOLIO

Web of Science

1.Jinan Univ, State Key Lab Bioact Mol & Druggabil Assessment, Guangzhou 510632, Peoples R China
2.Jinan Univ, Coll Pharm, Ctr Bioact Nat Mol & Innovat Drugs, Guangzhou 510632, Peoples R China
3.Jinan Univ, Coll Pharm, Guangdong Prov Key Lab Pharmacodynam Constituents, Guangzhou 510632, Peoples R China
4.Army Med Univ, Coll Pharm, Natl Engn Res Ctr Immunol Prod, Dept Microbiol & Biochem Pharm, Chongqing 400038, Peoples R China
5.Jinan Univ, Dept Med Lab, Shenzhen Peoples Hosp, Clin Med Coll 2, Shenzhen 518020, Guangdong, Peoples R China
6.Southern Univ Sci & Technol, Affiliated Hosp 1, Shenzhen 518020, Guangdong, Peoples R China
7.Southern Univ Sci & Technol, Shenzhen Grubbs Inst, Dept Chem, Shenzhen 518055, Guangdong, Peoples R China

Cheng, Min-Jing,Wu, Yan-Yi,Zeng, Hao,et al. Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA[J]. NATURE COMMUNICATIONS,2024,15(1).

Cheng, Min-Jing.,Wu, Yan-Yi.,Zeng, Hao.,Zhang, Tian-Hong.,Hu, Yan-Xia.,...&Wang, Lei.(2024).Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA.NATURE COMMUNICATIONS,15(1).

Cheng, Min-Jing,et al."Asymmetric total synthesis of polycyclic xanthenes and discovery of a WalK activator active against MRSA".NATURE COMMUNICATIONS 15.1(2024).