Synthesis of caprazamycin analogues and their structure--activity relationship for antibacterial activity.
Synthesis of palmitoyl caprazol 7, which possesses a simple fatty acyl side chain at the 3' ''-position of the diazepanone moiety, was carried out and their antibacterial activity was evaluated. The key elements of our approach include the improved synthesis of the key 5'-beta-O-aminoribosyl-glycyluridine derivative, installation of the palmitoyl side chain to the cyclization precursor, and the construction of the diazepanone by an intramolecular reductive amination. The second generation synthesis of (+)-caprazol was also established. Palmitoyl caprazol 7 exhibited antibacterial activity against Mycobacterium smegmatis ATCC607 (MIC = 6.25 microg/mL) with potency similar to that of the caprazamycins (CPZs). Palmitoyl caprazol 7 and N6'-desmethyl palmitoyl caprazol 28 also exhibited antibacterial activity against drug-resistant bacteria including methyciline-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) strains (MIC = 3.13-12.5 microg/mL).
Hirano
Shinpei
S
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
Ichikawa
Satoshi
S
Matsuda
Akira
A
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001381:Azepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013293:Enterococcus faecalis / Q000187:drug effects*; D005227:Fatty Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013211:Staphylococcus aureus / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014529:Uridine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
C527432:5'-beta-O-aminoribosyl-glycyluridine; D000900:Anti-Bacterial Agents; D001381:Azepines; D005227:Fatty Acids; C527431:palmitoylcaprazol; D014529:Uridine