Isoflavones from Maclura pomifera: structural elucidation and in silico evaluation of their interaction with PDE5.

While osajin and pomiferin are known for their anticancer, antibacterial and antidiabetic properties, scandenone and auriculasin have been proposed as anti-inflammatory and antinociceptive agents. Curiously, these two couples of molecules are, from a chemical point of view, structural isomers which can all be extracted from Maclura pomifera. Although previous works described, separately, the isolation in reasonable amounts of the sole osajin/pomiferin couple or of scandenone/auriculasin, we report the extraction and characterization using direct spectral and chromatographical comparison of the four compounds. 2D NMR allowed to unambiguously assign the correct structures to the isomers. The compounds were screened in silico against PDE5 and their interaction pattern with the protein was compared with that of icarisid II, a natural PDE5 inhibitor.

Semi-synthetic derivatives of natural isoflavones from Maclura pomifera as a novel class of PDE-5A inhibitors.

Natural (iso)flavonoids have been recently reported to inhibit cyclic nucleotide phosphodiesterases (PDEs) and induce vasorelaxation, albeit the results described in the literature are discordant. The cGMP-selective isoform PDE-5A, in particular, represents the target of sildenafil and its analogues in the treatment of erectile dysfunction (ED) and pulmonary hypertension by promoting relaxation in vascular smooth muscle through the activation of the NO/cGMP pathway. We undertook this study to verify if osajin and pomiferin, two natural prenylated isoflavones and major constituents of Maclura pomifera extracts previously investigated for their anticancer, antibacterial and antidiabetic properties, show inhibitory activity on PDE-5A. These two isoflavones were isolated from the plant extracts and then synthetically modified to obtain a set of semi-synthetic derivatives with slight and focused modifications on the natural scaffold. The compounds were at first screened against PDE-5A in vitro and, based on the encouraging results, further tested for their relaxant effect on isolated rat artery rings. Computational docking studies were also carried out to explore the mode of interaction with the target protein. The obtained data were compared to the behaviour of the well-known PDE-5A inhibitor sildenafil. Our results demonstrate that semi-synthetic derivatives of osajin and pomiferin show an inhibitory effect on the isolated enzyme that, for some of the compounds, is accompanied by a vasorelaxant activity. Based on our findings, we propose the here described isoflavones as potential lead compounds for the development, starting from natural scaffolds, of a new class of PDE-5A inhibitors with vasorelaxant properties.