YM-254890 analogues, novel cyclic depsipeptides with G$alpha;q/11 inhibitory activity from Chromobacterium sp. QS3666

Abstract

The structure elucidation and biological activity of novel YM-254890 (1) analogues and semi-synthetic derivatives are described. Three natural analogues, YM-254891 (2), YM-254892 (3), and YM-280193 (4), were isolated from the fermentation broth of Chromobacterium sp. QS3666, and two hydrogenated derivatives, YM-385780 (5) and YM-385781 (6), were synthesized from YM-254890. Their structures were determined by one- and two-dimensional NMR studies and mass spectrometry. Among these compounds, two natural analogues 2–3 which possessed acyl groups at β-HyLeu-1 and one derivative 6 whose conformation was similar to that of 1 showed comparable Gαq/11 inhibitory activity to that of 1. This indicates that the acyl β-HyLeu residue plays an important role in activity and also that the α,β-unsaturated carbonyl group of the N-MeDha residue is not critical to activity. The other hydrogenated derivative 5 had significantly less activity, which could be attributed to conformational differences.