Myxadazoles, Myxobacterium‐Derived Isoxazole–Benzimidazole Hybrids with Cardiovascular Activities

• Published in: Angewandte Chemie International Edition 2021-09, Vol.60 (40), p.21679-21684
• Main Authors: Li, Yuelan, Zhuo, Li, Li, Xiaobin, Zhu, Yongqiang, Wu, Shuge, Shen, Tao, Hu, Wei, Li, Yue‐Zhong, Wu, Changsheng
• Format: Article
• Language: English
• Subjects: Benzimidazoles; cardiovascular activities; Cardiovascular diseases; Coupling (molecular); Drug development; Drying; Fatty acids; Gene sequencing; Genomes; Hybridization; Hybrids; isoxazole–benzimidazole hybrids; Labeling; Metabolism; Microorganisms; molecular networking analysis; Mutation; myxadazoles; Natural products; NRPS gene; precursor-directed biosynthesis; Vitamin B12
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202106275

There is a continuous need for novel microbial natural products to fill the drying‐up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N‐ribityl 5,6‐dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non‐canonical PKS/NRPS gene cluster, whereas the origin of N‐ribityl 5,6‐dimethylbenzimidazole was related to the vitamin B12 metabolism. The convergence of these two distinct biosynthetic pathways through a C‐N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules with sound cardiovascular activities. Myxadazoles consist of a N‐ribityl 5,6‐dimethylbenzimidazole and a fatty acid chain endowed with an isoxazole ring. The fatty acid chain was encoded by a non‐canonical PKS/NRPS gene cluster, whereas the N‐ribityl 5,6‐dimethylbenzimidazole ring was originated from the endogenous vitamin B12 metabolism pathway. A plausible C−N cross coupling is likely to coordinate the convergence of these two distinct biosynthetic pathways that led to the final construction of the unique chemical scaffold of myxadazoles.