Total synthesis and antifungal evaluation of cyclic aminohexapeptides.
The need for new therapies to treat systemic fungal infections continues to rise. Naturally occurring hexapeptide echinocandin B (1) has shown potent antifungal activity via its inhibition of the synthesis of beta-1,3 glucan, a key fungal cell wall component. Although this series of agents has been limited thus far based on their physicochemical characteristics, we have found that the synthesis of analogues bearing an aminoproline residue in the 'northwest' position imparts greatly improved water solubility (> 5 mg/mL). The synthesis and structure-activity relationships (SAR) based on whole cell and upon in vivo activity of the series of compounds are reported.
Klein
L L
LL
Infectious Disease Research, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. larry.l.klein@abbott.com
Li
L
L
Chen
H J
HJ
Curty
C B
CB
DeGoey
D A
DA
Grampovnik
D J
DJ
Leone
C L
CL
Thomas
S A
SA
Yeung
C M
CM
Funk
K W
KW
Kishore
V
V
Lundell
E O
EO
Wodka
D
D
Meulbroek
J A
JA
Alder
J D
JD
Nilius
A M
AM
Lartey
P A
PA
Plattner
J J
JJ
D000208:Acute Disease; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002175:Candida / Q000187:drug effects; D002181:Candidiasis, Vulvovaginal / Q000188:drug therapy / Q000382:microbiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D054714:Echinocandins; D005260:Female; D005656:Fungal Proteins; D051379:Mice; D008826:Microbial Sensitivity Tests; D010455:Peptides; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011392:Proline / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000187:drug effects
D000588:Amines; D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D054714:Echinocandins; D005656:Fungal Proteins; D010455:Peptides; D010456:Peptides, Cyclic; D000666:Amphotericin B; D011392:Proline; C007572:echinocandin B