Design and Biosynthesis of Dimeric Alboflavusins with Biaryl Linkages via Regiospecific C–C Bond Coupling

• DOI: 10.1021/jacs.8b10136
• Publication Date: 2018-12-05T19:17:55Z
• Authors: Zhengyan Guo; Pengwei Li; Guozhu Chen; Chao Li; Zhenju Cao; Yuwei Zhang; Jinwei Ren; Hua Xiang; Shuangjun Lin; Jianhua Ju; Yihua Chen
• Keywords: 01 natural sciences; 0104 chemical sciences

Alboflavusins (AFNs) are a group of cyclohexapeptides with moderate antibacterial and antitumor activities from Streptomyces alboflavus sp. 313. In vivo and in vitro studies proposed that AFNs are biosynthesized by a nonribosomal peptide synthetase machinery, and the 6-Cl-L-Trp precursor is supplied by a tryptophan halogenase gene located outside the afn gene cluster. Guided by the structure-activity relationship knowledge about the AFN-like cyclohexapeptides, two dimeric AFNs (di-AFNs) with regiospecific biaryl linkages were designed and generated biotechnologically by expressing the P450 gene hmtS or clpS in S. alboflavus wild-type and mutant strains. The di-AFNs displayed much better antibacterial and antitumor activities than their monomers as anticipated, exemplifying a rational strategy to generate natural product congeners with improved bioactivities.