Restricted Conformation Analogues of an Anthelmintic Cyclodepsipeptide

Six analogues of the anthelmintic cyclodepsipeptide PF1022A were prepared, each containing a small ring fused to the macrocycle to restrict the number of conformations the larger ring can adopt. It was anticipated that such conformational changes could lead to enhanced biological activity and select...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2003-05, Vol.46 (11), p.2057-2073
Main Authors: Dutton, Fred E, Lee, Byung H, Johnson, Sandra S, Coscarelli, Eileen M, Lee, Pil H
Format: Article
Language:English
Subjects:
Animals
Anthelmintics - chemical synthesis
Anthelmintics - chemistry
Anthelmintics - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiparasitic agents
Biological and medical sciences
Depsipeptides
Gerbillinae
Haemonchus - drug effects
Medical sciences
Models, Molecular
Molecular Conformation
Peptides, Cyclic - chemical synthesis
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:Six analogues of the anthelmintic cyclodepsipeptide PF1022A were prepared, each containing a small ring fused to the macrocycle to restrict the number of conformations the larger ring can adopt. It was anticipated that such conformational changes could lead to enhanced biological activity and selectivity. The analogues form two series of three members each. In one series, a carbon-based molecular bridge joins the methyl of a leucine residue with the methyl of its closest lactic acid residue to form five-, six-, and seven-membered lactam rings. In the second series, a leucine residue is replaced with five-, six-, and seven-membered nitrogen heterocycles. Decreasing the size of the small ring in the lactam series increasingly distorts the macrocycle and consistently decreases activity relative to PF1022A. In the leucine series, a similar trend is observed. Molecular modeling of PF1022A along with the analogues described herein suggests that the ability to exist in a highly symmetrical conformational state is a necessary condition for biological activity.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020482k