Tetra-cis/trans-Coumaroyl Polyamines as NK1 Receptor Antagonists from Matricaria chamomilla

Cis-trans isomers of N 1,N 5,N 9,N 14-tetra-p-coumaroyl thermospermines and N 1,N 5,N 10,N 14-tetra-p-coumaroyl spermines were found in Matricaria chamomilla, German chamomile using countercurrent chromatography with methylene chloride-methanol-water (1:1:1, v/v/v). Their structures were elucidated based on spectroscopic and spectrometric data (1D and 2D NMR, and HRESIMS). The antagonistic activity against the neurokinin-1 receptor was examined by a calcium assay, measuring the cytosolic fluorescence triggered by substance P binding to the receptor. The compounds 1a/1b, 2a/2b, and 3a/3b potently suppressed the calcium flux compared to the known antagonist L-703,606 oxalate, indicating that the compounds competitively inhibited the binding of substance P. They also suppressed substance P-induced proliferation in MDA-MB-453, the HER2-amplified breast cancer cell line. It is suggested that tetracoumaroyl thermospermines and tetracoumaroyl spermines are promising antagonists, exerting positive effects on substance P/neurokinin-1 receptor-related diseases.