Enzymatic synthesis and immunosuppressive activity of novel desmethylated immunomycins (ascomycins).
31-O-Desmethylimmunomycin O: methyltransferase (DIMT), an enzyme involved in the biosynthesis of immunomycin (ascomycin/FR-900520), was used to synthesize three analogs of this immunosuppressant compound. These compounds were assigned the following structures: 13-O-desmethyl-, 15-O-desmethyl- and 13,15-O-bisdesmethyl-immunomycins. Two of these compounds, namely, 15-O-desmethyl- and 13,15-O-bismethyl-immunomycins have novel structures and were examined for possible immunosuppressive activity by in vitro T-cell proliferation assay. The results showed that methylation of the C-15 hydroxyl is critical for full biological activity of the immunomycin.
Shafiee
A
A
Merck Research Laboratories, Rahway, NJ 07065.
Chen
T S
TS
Arison
B S
BS
Dumont
F J
FJ
Colwell
L
L
Kaplan
L
L
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D004798:Enzymes / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008745:Methylation; D051379:Mice; D008810:Mice, Inbred C57BL; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D004798:Enzymes; D007166:Immunosuppressive Agents; C084048:15-O-desmethylascomycin; C084049:13-O-desmethylascomycin; C084050:13,15-O-bidesmethylascomycin; D016559:Tacrolimus