Journal of Medicinal Chemistry p. 2843 - 2855 (1992)
Update date:2022-07-30
Topics:
Zambias, Robert A.
Hammond, Milton L.
Heck, James V.
Bartizal, Ken
Trainor, Charlotte
et al.
The echinocandins are a well-known class of lipopeptides characterized by their potent antifungal activity against Candida species.The mechanism of action of the echinocandins is generally thought to be the inhibition of β-1,3-glucan synthesis, an important structural component in the cell wall of Candida species.Extensive structure-activity studies on the fatty acid side chain of echinocandin B (1) led to the preparation of the clinical candide cilofungin (4).However, little is known about the cyclic peptide.We now report the preparation, by solid-phase synthesis, of a series of simplified analogs of cilofungin in which the unusual amino acids found in the echinocandins were replaced with more readily accesible natural amino acids.The solid-phase approach to the total synthesis of these analogs allowed us to conveniently explore structural modifications that could not be accomlished by chemical modification of the natural product.The simplest analog 5 showed no biological activity.Structural complexity was then returned to the sytem in a systematic fashion so as to reapproach the original cilofungin structure.Antifungal activity and the inhibition of β-1,3-glucan synthesis were monitored at each step of the process, thereby revealing the basic structure-activity relationships of the amino acids and the minimal structural requirements for biological activity in the echinocandin ring system.The results suggests that the 3-hydroxy-4-methylproline residue enhances activity but the L-homotyrosine residue is crucial for both antifungal activity and the inhibition of β-1,3-glucan synthesis.
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Doi:10.1016/0040-4039(92)88143-S
(1992)Doi:10.1021/ja00039a079
(1992)Doi:10.1016/j.tetlet.2012.12.055
(2013)Doi:10.1002/anie.201204538
(2012)Doi:10.1016/j.jorganchem.2012.11.007
(2013)Doi:10.1016/0040-4039(92)88140-Z
(1992)