Preparation and structure-activity relationships of simplified analogs of the antifungal agent cilofungin: a total synthesis approach

Abstract

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 beta-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 candidate 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 accessible 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 accomplished by chemical modification of the natural product. The simplest analog 5 showed no biological activity. Structural complexity was then returned to the system in a systematic fashion so as to reapproach the original cilofungin structure. Antifungal activity and the inhibition of beta-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 beta-1,3-glucan synthesis.

Future therapies targeted towards eliminatingCandidabiofilms and associated infections

“… Echinocandins are semisynthetic lipopeptides with a central cyclic hexapeptide structure [241].  non-competitively inhibit a principal cell wall structural constituent, 1,3-beta-D-glucan ( Figure 2) leading to static destabilization of the fungus causing osmotic cell lysis [242,243].…”

Novel Insights into the Mode of Inhibition of Class A SHV-1 β-Lactamases Revealed by Boronic Acid Transition State Inhibitors

“…Compounds 1 and 2 were obtained in two steps according to the scheme shown in Fig. 1B by using the appropriate amino acids (D-homotyrosine, synthesized as hydrobromide from D-aspartic acid [15,28], and commercially available D-tyrosine, respectively), commercially available 4-ethyl-2,3-dioxopiperazine-1-carbonyl chloride, and bis-(trimethylsilyl)-aminomethaneboronate, synthesized as previously described (7).…”

Use of cilofungin as direct fluorescent probe for monitoring antifungal drug-membrane interaction

“…The emission spectrum of the 1:1 mixture of HBA and NATA, which reflects the actual ratio of chro-VOL. 38 mophores in cilofungin, was clearly different from that of cilofungin in both relative intensity and spectral position (Fig. 4).…”

“…A number of antifungal drugs have been targeted against GSs from various fungi including the lipopeptide echinocandin-like class of inhibitors (12,30,31,35), aculeacin A (23,24), cilofungin (8,10,11), pneumocandins (12,31), and the papulacandins (2,16,26,37), which are lipid-like saccharides. Each of these compounds contains fatty acid side chains, which have been shown to be essential for the actions of cilofungin (34,38) and papulacandin B (37). Although various lipophilic compounds are known to rapidly inactivate fungal glucan (18,25) and chitin synthases (25), the mechanism by which these compounds interfere with GS has only recently begun to attract considerable attention (17,18,36).…”