Solid-phase synthesis of dihydrovirginiamycin S1, a streptogramin B antibiotic.
We describe the first solid-phase synthesis of dihydrovirginiamycin S(1), a member of the streptogramin B family of antibiotics, which are nonribosomal-peptide natural products produced by Streptomyces. These compounds, along with the synergistic group A components, are "last line of defense" antimicrobial agents for the treatment of life-threatening infections such as vancomycin-resistant enterococci. The synthesis features an on-resin cyclization and is designed to allow production of streptogramin B analogues with diversification at positions 1', 1, 2, 3, 4, and 6. Several synthetic challenges known to hinder the synthesis of this class of compounds were solved, including sensitivity to acids and bases, and epimerization and rearrangements, through the judicious choice of deprotection conditions, coupling conditions, and synthetic strategy. This work should enable a better understanding of structure-activity relationships in the streptogramin B compounds, possible identification of analogues that bypass known resistance mechanisms, and perhaps the identification of analogues with novel biological activities.
Shaginian
Alex
A
Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Rosen
Marissa C
MC
Binkowski
Brock F
BF
Belshaw
Peter J
PJ
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects; D003500:Cyclization; D007202:Indicators and Reagents; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D008968:Molecular Conformation; D025381:Streptogramin B / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D025382:Streptogramin Group B / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014769:Virginiamycin / Q000138:chemical synthesis* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D007202:Indicators and Reagents; D025382:Streptogramin Group B; D014769:Virginiamycin; D025381:Streptogramin B; C418083:virginiamycin factor S1