First Y-type actinomycins from Streptomyces with divergent structure-activity relationships for antibacterial and cytotoxic properties.
Streptomyces sp. strain Gö-GS12 was found to produce five novel actinomycins Y(1)-Y(5) (). Their amino acid pattern discloses them as members of a new family of this important class of antibiotics. Compounds differ from Z-type actinomycins in their beta-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 beta-ring can undergo rearrangement by a two-fold acyl shift (compounds and ) or show a unique additional ring closure with the chromophore (compound ), resulting in metabolites with yet unknown structural motifs, altered conformations and distinct bioactivities. The strongest bioactivity was found for the chlorine containing actinomycin Y(1) (), the most surprising for Y(5) () with cytotoxic and antibacterial effects losing their coherence, which has been observed for the first time here.
Bitzer
Jens
J
Institute of Organic and Biomolecular Chemistry, University of Göttingen, Tammannstr.2, D-37077, Göttingen, Germany.
Streibel
Martin
M
Langer
Hans-Jörg
HJ
Grond
Stephanie
S
D000596:Amino Acids / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000096:biosynthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects; D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D003609:Dactinomycin / Q000096:biosynthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism; D013302:Streptomyces / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000596:Amino Acids; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D003603:Cytotoxins; D003609:Dactinomycin