Abstract
A new resveratrol dimer (1) called labruscol, has been purified by centrifugal partition chromatography of a crude ethyl acetate stilbene extract obtained from elicited grapevine cell suspensions of Vitis labrusca L. cultured in a 14-liter stirred bioreactor. One dimensional (1D) and two dimensional (2D) nuclear magnetic resonance (NMR) analyses including 1H, 13C, heteronuclear single-quantum correlation (HSQC), heteronuclear multiple bond correlation (HMBC), and correlation spectroscopy (COSY) as well as high-resolution electrospray ionisation mass spectrometry (HR-ESI-MS) were used to characterize this compound and to unambiguously identify it as a new stilbene dimer, though its relative stereochemistry remained unsolved. Labruscol was recovered as a pure compound (>93%) in sufficient amounts (41 mg) to allow assessment of its biological activity (cell viability, cell invasion and apoptotic activity) on two different cell lines, including one human skin melanoma cancer cell line HT-144 and a healthy human dermal fibroblast (HDF) line. This compound induced almost 100% of cell viability inhibition in the cancer line at a dose of 100 μM within 72 h of treatment. However, at all tested concentrations and treatment times, resveratrol displayed an inhibition of the cancer line viability higher than that of labruscol in the presence of fetal bovine serum. Both compounds also showed differential activities on healthy and cancer cell lines. Finally, labruscol at a concentration of 1.2 μM was shown to reduce cell invasion by 40%, although no similar activity was observed with resveratrol. The cytotoxic activity of this newly-identified dimer is discussed.
Highlights
Stilbenoids, which are naturally-occurring secondary metabolites widely represented in the plant kingdom, can be divided into monomeric and oligomeric compounds [1]
V. labrusca cultured in a 14-L stirred bioreactor was fractionated by centrifugal partition chromatography (CPC) in a single run of 160 min using a normal phase gradient elution method, including a biphasic solvent system composed of n-heptane, ethyl acetate, methanol and water in the ascending mode
CPC is a solid support-free separation technique involving the differential partition of solutes between at least two immiscible liquid phases according to their distribution coefficient [16]
Summary
Stilbenoids, which are naturally-occurring secondary metabolites widely represented in the plant kingdom, can be divided into monomeric and oligomeric compounds [1]. The most studied stilbene monomer is resveratrol and its biological activity as a phytoalexin in plants or its preventing action against human diseases has already led to a considerable number of works. Limitations in studying the biological properties of resveratrol dimers essentially reside in the difficulty to recover these compounds in large amounts by using conventional plant extraction procedures or chemical synthesis. Cultivating grapevine cells in bioreactors in the presence of various defense-inducing compounds, the so-called elicitors [11,12,13,14,15], has been shown to constitute a useful technique for the production of tens to hundreds milligrams of dimeric stilbenes with high purity [9]. We report on the characterization of a new stilbene dimer called labruscol (1) produced by grapevine cell suspensions of Vitis labrusca L. var. Its properties were compared to those of a resveratrol bioproduced from the same cell suspensions
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