Natural-echinocandins

WFl 1899A, B and C (Fig.37) were discovered by Iwamoto et al. in 1994 as water-soluble antifungal compounds from Coleophoma empetri F-11899. These compounds contain a sulfate residue in their structure, while other natural-echinocandins do not. Replacement of the sulfate residue in WF11899A by an arylsulfate greatly diminishes its water solubility, indicating that its excellent water solubility is attributed to the sulfate residue ... 

One example of the utilization of this approach for the synthesis of natural products is the facile access, Fig. 10, to the southwest tripeptide segment of echinocandin B, 148, a cyclic hexapeptide that is characterized by its antifungal and antiyeast activity. 

Kurokawa and Ohfune [71] employ i DPPA in the synthesis of the hexapeptide echinocandin D 125). As shown in Scheme 42, the cyclization of the Unear peptide 124 was accomplished by DPPA to give 125 in 50% yield. There are more applications of DPPA in the synthesis of macrocycUc natural products [72]. DEPC is relatively less commonly used than DPPA. Kishi and coworkers [73] have successfully achieved the synthesis of the macrocyclic antibiotic rifamycin S using DEPC as a macrolactamization promoter. 

Figure I Representatives of the six naturally occurring families of echinocandin lipopeptide antifungal agents.

Antifungal agents of the echinocandin class (both natural products and seroisynthetic analogs) chat have been studied to dace are inhibitors of fungal wall biosynthesis. They... 

All natural product members of the echinocandin class have a cyclic hexapeptide ring with a fatty acid side chain attached to the a-amino-group of the ornithine. All members contain an unusual, hydroxyl-substituted, homotyrosine residue, two substi-... 

Of the six naturally occurring echinocandin families, only the original echinocandins and the pneumocandins have been subjected to extensive structure-activity studies by synthetic alteration. Structure-activity work based on WFl 1899 has been conducted by scientists at Fujisawa, but only limited data was found in the patent literature at the time of this writing (30,31). The remainder of this section describes the structure-activity studies of the echinocandin and pneumocandin derivatives. 

Figure 9 Structures of naturally occulting and selected semisynthecic analogs of compounds in the pneutnocandin family of echinocandins.

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