Monoterpenoid 5-methylcoumarins from Centrapalus pauciflorus with antiproliferative activity

Abstract

Thirteen undescribed monoterpene-fused 5-methylcoumarins, named centrapalus coumarins A–M, were isolated from the aerial parts of the Centrapalus pauciflorus together with seven known compounds. The structures were established by extensive spectroscopic analyses, including 1D NMR, 2D NMR, and HR-ESI-MS experiments. The compounds represent a wide range of chemical diversity depending on the connection of the head-to-tail coupled diisoprene unit. Centrapalus coumarins A–H and I–L are based on 6–6–6- and 6–6-7-membered tricyclic ring systems, respectively. Centrapalus coumarins D and E exhibit cyclic hemiketal structures, while centrapalus coumarins F is unique because its monoterpene part forms an additional lactone ring. Centrapalus coumarin L is the only compound containing a modified trinor-monoterpene part. Centrapalus coumarin M is unprecedented as it contains a pentacyclic heterocyclic ring system. Sixteen isolated compounds were investigated for antiproliferative activity on the human breast (MCF-7 and MDA-MB-231), cervical (HeLa and SiHa), and ovarian (A2780) cancer-cell lines by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and a few of them exhibited substantial activity. Centrapalus coumarin F demonstrated the highest potency against MCF-7, HeLa, and A2780 cells with IC50 values of 6.59, 2.28, and 15.41 μM, respectively. The cytotoxic activity of centrapalus coumarin F showed moderate cancer selectivity, as determined using intact fibroblast cells (NIH-3 T3). The antiproliferative activity of these 5-methylcoumarin derivatives provides evidence for the establishment of structure–activity relationships.