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

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

  • Nat Commun. 2024 Jul 13;15(1):5879. doi: 10.1038/s41467-024-49629-8.
Min-Jing Cheng # 1 2,  Yan-Yi Wu # 1 2,  Hao Zeng # 3,  Tian-Hong Zhang 1 2,  Yan-Xia Hu 1 2,  Shi-Yi Liu 4,  Rui-Qin Cui 4,  Chun-Xia Hu 4,  Quan-Ming Zou 5,  Chuang-Chuang Li 6,  Wen-Cai Ye 7 8,  Wei Huang 9,  Lei Wang 10 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, P. R. China.
  • 2 Center for Bioactive Natural Molecules and Innovative Drugs, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China.
  • 3 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing, 400038, P. R. China.
  • 4 Department of Medical Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.
  • 5 National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Army Medical University, Chongqing, 400038, P. R. China. qmzou2007@163.com.
  • 6 Department of Chemistry, Shenzhen Grubbs Institute, Southern University of Science and Technology, Shenzhen, 518055, P. R. China. ccli@sustech.edu.cn.
  • 7 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, P. R. China. chywc@aliyun.com.
  • 8 Center for Bioactive Natural Molecules and Innovative Drugs, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China. chywc@aliyun.com.
  • 9 Department of Medical Laboratory, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China. whuang_sz@163.com.
  • 10 State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, P. R. China. cpuwanglei@126.com.
  • 11 Center for Bioactive Natural Molecules and Innovative Drugs, and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, P. R. China. cpuwanglei@126.com.
  • # Contributed equally.
PMID: 38997253 DOI: 10.1038/s41467-024-49629-8
Abstract

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.

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