Prodigiosin R3, a new multicyclic prodigiosin formed by prodigiosin cyclization genes in the roseophilin producer

The rph gene cluster for prodigiosin biosynthesis has been identified in Streptomyces griseoviridis 2464-S5, which produces cyclic prodigiosin derivatives including roseophilin (2), prodigiosin R1 (3) and prodigiosin R2 (4). A new cyclic prodigiosin, prodigiosin R3 (1), was produced by the redG redP double disruptant of Streptomyces coelicolor M511 expressing four cyclization gene candidates (rphG, rphG2, rphG3 and rphG4) in the rph cluster. The same compound was isolated from Streptomyces griseoviridis 2464-S5. The molecular formula of 1 was established as C₂₇H₃₃N₃O by ESI and FAB mass spectrometry. The structure was determined to be a multicyclic prodigiosin with three alkyl linkages by NMR spectroscopic analysis. Prodigiosin R3 (1) showed cytotoxicity against HeLa human cervical carcinoma cells and HT1080 human fibrosarcoma cells with IC₅₀s of 2.1 µM and 3.2 µM, respectively.