Relationship between structure and biological activity of novel R106 analogs.

The retro-aldol reaction at residue 8 of R106-1 produced a chemical handle, in the form of a sarcosine residue, that was amenable to classical aldol alkylation conditions. In vitro assay of several new hydroxylated analogs have shown that L isomers exhibit more potent antifungal activity than D isomers. However, all analogs exhibited a significant decrease in activity against Cryptococcus neoformans. By contrast, structural modifications of R 106 were tolerated by some Candida spp., but the potency of activity was diminished as compared to that of the natural product R106-1. The full structure-activity relationship of the new R106 analogs has provided important information about the steric and electronic requirements of binding to target receptors. Furthermore, comparison of the structural differences between R106-1 and other derivatives, suggested that the potential for hydrogen bonding (at residue 8) was a key structural feature that was required to maintain activity against Cryptococcus neoformans.