YM-254890 analogues, novel cyclic depsipeptides with Galpha(q/11) inhibitory activity from Chromobacterium sp. QS3666.
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 beta-HyLeu-1 and one derivative 6 whose conformation was similar to that of 1 showed comparable Galpha(q/11) inhibitory activity to that of 1. This indicates that the acyl beta-HyLeu residue plays an important role in activity and also that the alpha,beta-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.
Taniguchi
Masatoshi
M
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21, Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. taniguti@yamanouchi.co.jp
Suzumura
Ken-Ichi
K
Nagai
Koji
K
Kawasaki
Tomihisa
T
Takasaki
Jun
J
Sekiguchi
Mitsuhiro
M
Moritani
Yumiko
Y
Saito
Tetsu
T
Hayashi
Kazumi
K
Fujita
Shigeo
S
Tsukamoto
Shin-Ichi
S
Suzuki
Ken-Ichi
K
D000244:Adenosine Diphosphate / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002861:Chromobacterium / Q000737:chemistry*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006865:Hydrogenation; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1
C546382:P2RY1 protein, human; D010456:Peptides, Cyclic; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; C475455:YM-254890; D000244:Adenosine Diphosphate; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D002118:Calcium