First Y-type actinomycins from Streptomyces with divergent structure-activity relationships for antibacterial and cytotoxic properties.

Streptomyces sp. strain Go-GS12 was found to produce five novel actinomycins Y1–Y5 (1–5). Their amino acid pattern discloses them as members of a new family of this important class of antibiotics. Compounds 1–5 differ from Z-type actinomycins in their β-peptidolactone rings which here contain trans-4-hydroxyproline (Hyp) or 4-oxoproline (OPro) amino acids, and from the X-congeners by containing methylalanine (MeAla). Within the new Y-type actinomycins variations are not only in the rare chlorinated or hydroxylated threonine residue. Furthermore, the β-ring can undergo rearrangement by a two-fold acyl shift (compounds 3 and 4) or show a unique additional ring closure with the chromophore (compound 5), resulting in metabolites with yet unknown structural motifs, altered conformations and distinct bioactivities. The strongest bioactivity was found for the chlorine containing actinomycin Y1 (1), the most surprising for Y5 (5) with cytotoxic and antibacterial effects losing their coherence, which has been observed for the first time here.