Synthesis and evaluation of oxodioxolenylmethyl carbamate prodrugs of pseudomycins.
With the aim of increasing therapeutic indexes of novel cyclic depsinonapeptide pseudomycins, we synthesized and evaluated a series of mono-, di-, and trioxodioxolenylmethyl carbamate prodrugs (2 and 4) of pseudomycin B 1 and pseudomycin C' 3. It is rather encouraging to note that several members of the newly synthesized prodrugs described herein (e.g., 2a, 2e, and 4e) exhibited comparable in vivo efficacy to that achieved by the parent compounds, yet free of tail vein irritation and histamine induced toxicity in vivo.
Sun
X
X
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Rodriguez
M
M
Zeckner
D
D
Sachs
B
B
Current
W
W
Boyer
R
R
Paschal
J
J
McMillian
C
C
Chen
S H
SH
D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002177:Candidiasis / Q000188:drug therapy; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004149:Dioxoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006636:Histamine Release / Q000187:drug effects; D016867:Immunocompromised Host; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D013329:Structure-Activity Relationship; D013623:Tail / Q000098:blood supply; D014680:Veins / Q000187:drug effects
D000935:Antifungal Agents; D002219:Carbamates; D004149:Dioxoles; D010456:Peptides, Cyclic; D011355:Prodrugs; C425223:pseudomycin B; C425226:pseudomycin C'