Hydnocarpin-Type Flavonolignans: Semisynthesis and Inhibitory Effects on Staphylococcus aureus Biofilm Formation

Abstract

A new, efficient, and general semisynthesis of hydnocarpin-type flavonolignans was developed and optimized, enabling gram-scale production of hydnocarpin D (2). Moreover, the syntheses of optically pure hydnocarpin isomers [(10R,11R)-hydnocarpin (1a), (10R,11R)-hydnocarpin D (2a), and (10S,11S)-hydnocarpin D (2b)], as well as the synthesis of isohydnocarpin (8), were achieved for the first time utilizing this new method. The synthesis is based on the two-step transformation of the readily available flavonolignans from milk thistle (Silybum marianum), accessible by isolation from the commercial extract silymarin. The first step relies on the regioselective formylation of the C-3 hydroxy group of the dihydroflavonol-type precursor using the Vilsmeier-Haack reagent, followed by formic acid elimination by triethylamine in the second step. The synthesized compounds were effective inhibitors of Staphylococcus aureus biofilm formation, with (10S,11S)-hydnocarpin D (2b) being the most potent inhibitor. Furthermore, the effect of glucose on biofilm formation was tested, and glucose decreased the biofilm inhibitory activity of 2b. Moreover, 2b increased the susceptibility of Staph. aureus to enrofloxacin.

Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins

“…We measured optical rotations and ECD and confirmed the proposed structures (see Figures S3 and S4 in Supporting Information File 1 ). To our knowledge, this is the second case only [ 22 ] that these two enantiomers were obtained as pure and fully characterized compounds, namely by chiroptical methods. It should be mentioned that previous studies on hydnocarpin D failed to determine its absolute configuration.…”

“…Evaluation of Mitsunobu conditions and reagents applied for esterification and dehydration, respectively, enabled us to exclusively obtain either the hydnocarpin compound esters (and therefore hydnocarpin-type compounds after hydrolysis) or esterification. The recently reported method by Vimberg et al [ 22 ], that was published during the preparation of this article, describes a four-step synthesis using Vilsmeier–Haack conditions. Our study exhibits good atom economics and remains the only specific application of Mitsunobu conditions for a one-pot dehydration of this important class of natural products.…”

“…A very recent example of conversion of silybins to hydnocarpins was described by Vimberg et al, who applied a four-step synthesis and used Vilsmeier–Haack conditions ( Fig. 2 ) [ 22 ]. Before this, the only reference for the synthetic preparation of hydnocarpin D used coniferyl alcohol and luteolin as starting materials, and obtained hydnocarpin D as a minor product only (7%, catalyzed by Ag 2 CO 3 ; 5% catalyzed by horseradish peroxidase) [ 14 ].…”

Effects of Lonicera japonica Flower Bud Extract on Citrobacter rodentium-Induced Digestive Tract Infection

“…LJF has been reported to contain loniceroside, loganin, hydnocarpin, and luteolin, among other components [32][33][34]. Hydnocarpin has been reported to show antibacterial effects against Staphylococcus aureus by suppressing biofilm formation [35]. Moreover, loniceroside has been reported to show immunomodulatory effects through its anti-inflammatory activity [36].…”

Anti-virulence Strategies to Target Bacterial Infections

“…In addition, diverse small molecule inhibitors of biofilm formation have been identified. These include hydnocarpin-type flavonolignans and streptorubin B for S. aureus and cyclosporine and valspodar, for Streptococcus biofilm inhibition (Aggarwal et al 2015;Suzuki et al 2015;Vimberg et al 2015).…”