Cpumycins A-C, Aminated Benzoic Dimers from Streptomyces sp. CPU-W6, and Their Potential Cardioprotective Activities

Chemical investigation of the soil-derived actinomycete Streptomyces sp. CPU-W6 led to the discovery of three novel aminated benzoic dimers, cpumycins A-C (1-3). Their structures, featuring a distinctive C-N-C-linked heterodimeric skeleton, were determined through extensive spectroscopic techniques and X-ray diffraction. Bioinformatic analysis and targeted gene deletions identified a shikimate-derived biosynthetic gene cluster (CPU BGC) responsible for the assembly of these metabolites. Further investigations revealed that the formation of cpumycins 1 and 2 follows a hybrid "enzymatic-plus-spontaneous" biosynthetic paradigm, in which the enzymatic production of shikimate-derived aromatic precursors is coupled with a pH-dependent, spontaneous dimerization. In biological assays, cpumycins B (2) and C (3) exhibited cytoprotective effects against CoCl₂-induced injury in undifferentiated H9c2 cells at nanomolar concentrations, while exhibiting negligible cytotoxicity (IC₅₀ > 620 μM). These findings significantly expand the chemical diversity of shikimate-derived microbial metabolites and provide promising lead scaffolds for the development of therapeutics with potential cardioprotective benefits.