Late-Stage Tailoring Steps in the Biosynthesis of β-Rubromycin Involve Successive Terminal Oxidations, a Selective Hydroxyl Reduction, and Distinctive O-Methylations

• Published in: Organic letters 2024-12
• Main Authors: Yi, Liwei, Yi, Sirun, Wang, Yeji, Kong, Jieqian, Xiong, Yi, Zhou, Yusheng, Duan, Yanwen, Zhu, Xiangcheng
• Format: Article
• Language: English
• ISSN: 1523-7052; 1523-7052
• DOI: 10.1021/acs.orglett.4c03965

β-Rubromycin ( ) has a unique O-methylated naphthoquinone moiety and is an efficient inhibitor of human telomerase. Through and investigations, we elucidated the biosynthetic tailoring steps of compound , which involve the carboxyl terminal via successive oxidizations by RubU and RubO1/RubO2, O-methylation of the carboxyl terminal by RubX, and reduction of C-3' hydroxyl by RubK. The final tautomerization of the naphthoquinone moiety is mediated by RubO, which anchors the transitional intermediate through O-methylation to form the naphthoquinone tautomer. The structure-activity relationship further revealed the significant influences of the terminal modification status on anticancer activities of rubromycins.