Synthesis, cytotoxicity, and pyoverdine production inhibitory activity of actinomycin lactam analogs

Pyoverdines are fluorescent siderophores and potential virulence factors produced by Pseudomonas bacteria. Actinomycin D has been reported to inhibit pyoverdine production; however, its strong cytotoxicity limits its use as a probe to elucidate pyoverdine function. In this study, we synthesized actinomycin analogs (1–4) with modified phenoxazine moiety. To enable convergent syntheses, the threonine residues were replaced with 2,3-diaminopropionic acid. Compound 1–4 showed negligible to low cytotoxicity toward HHUA endometrial cancer cells. However, only 4, with the same phenoxazine ring as actinomycin D, retained inhibitory activity against pyoverdine production by Pseudomonas fluorescence NBRC15833, although an order of magnitude lower than actinomycin D. These results suggest that the phenoxazine ring would be essential to the cytotoxicity and pyoverdine production inhibitory activity, and the further modification of cyclic peptide moiety is necessary to understand the structure-activity relationship underlying pyoverdine production inhibition.