title: Semi-synthetic derivatives of natural isoflavones from Maclura pomifera as a novel class of PDE-5A inhibitors.
abstract: 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.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ribaudo
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Mario Angelo
authors.initials: MA
authors.lastname: Pagano
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pavan
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Redaelli
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Maira
authors.initials: M
authors.lastname: Zorzan
authors.affiliation: Department of Medicine, University of Padova, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Pezzani
authors.affiliation: Department of Molecular Medicine, University of Padova, Padova, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Mucignat-Caretta
authors.affiliation: Accademia Trevigiana per il Territorio, Treviso, Italy.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Vendrame
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy. Electronic address: giuseppe.zagotto@unipd.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry* / Q000302:isolation & purification; D066298:In Vitro Techniques; D007529:Isoflavones / Q000737:chemistry* / Q000302:isolation & purification; D031624:Maclura / Q000737:chemistry*; D008297:Male; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058986:Phosphodiesterase 5 Inhibitors / Q000737:chemistry* / Q000302:isolation & purification; D010936:Plant Extracts / Q000737:chemistry; D051381:Rats; D011921:Rats, Inbred WKY; D014665:Vasodilator Agents / Q000737:chemistry* / Q000302:isolation & purification
chemical_list: D001578:Benzopyrans; D007529:Isoflavones; D058986:Phosphodiesterase 5 Inhibitors; D010936:Plant Extracts; D014665:Vasodilator Agents; C474837:pomiferin; C485800:osajin
keywords: Erectile dysfunction; Isoflavones; Maclura pomifera; Osajin (PubChem CID: 95168); PDE-5A; Pomiferin (PubChem CID: 4871); Sildenafil