Isolation, bioassay and 3D-QSAR analysis of 8-isopentenyl flavonoids from Epimedium sagittatum maxim. as PDE5A inhibitors

Abstract

Background As known, inhibition of phosphodiesterase 5 (PDE5) has the therapeutic effect on male erectile dysfunction (ED), and the processed folium of Epimedium sagittatum Maxim. (PFES) characterized by 8-isopentenyl flavonoids is a famous herb for treating ED. However, the main flavonoids inhibitory activities, structure–activity relationship (SAR) and signaling pathway have been not systematically studied so that its pharmacodynamic mechanism is unclear. Methods We aimed to initially reveal the PFES efficacy mechanism for treating ED. For the first time, 6 main 8-isopentenyl flavonoids (1–6) from PFES were isolated and identified. Then based on HPLC detection, we proposed a novel method to screen inhibitors among them. We further analyze the three-dimensional quantitative structure–activity relationship (3D-QSAR) for those inhibitors. Results The results were verified by cellular effects of the screened flavonoids. Among 6 compounds, Icariin: (1), 2-Oʹʹrhamnosylicaridide II (2) and Baohuoside I (3) were identified with significant activities (IC50 = 8.275, 3.233, 5.473 μM). Then 3D-QSAR studies showed that the replacement of C8 with bulky steric groups as isopentenyl, C3 with positive charge groups and C4' with a hydrogen bond acceptor substituent could increase inhibitory effects. In contrast, the substitution of C7 with bulky steric groups or hydrophilic groups tended to decrease the efficacies. And compounds 1, 2, 3 could increase cGMP level and decrease cytoplasmic Ca2+ of rat corpus cavernosum smooth muscle cells (CCSMCs)by activating PKG. Conclusion 8-isopentenyl flavonoids could be the main pharmacodynamic substances of PFES in the treatment for ED, and some had significant PDE5A1 inhibitory activities so as to activate cGMP/PKG/Ca2+ signaling pathway in CCSMCs, that was related to the substituents at the key sites such as C8, C3, C4ʹ and C7 in the characteristic compounds.

Exploring effect of herbal monomers in treating gouty arthritis based on nuclear factor-kappa B signaling: A review

“…The presence of an isoprenyl group on C-8 in its molecular structure is important to ensure its anti-inflammatory, antioxidant, and other effects. [ 45 , 46 ] Luteolin is a natural pigment with a basic chemical structure that includes phenyl rings, flavonols with multiple double bonds, and an epoxy group. Its antioxidant activity and other pharmacological effects are widely believed to be affected by the 1,4-pyrone moiety and the 3-OH group.…”

Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases

“…PDE5 inhibition, leading to increased cGMP levels [47]. In addition, flavonoid aglycones may increase the expression and activity of endothelial NO-synthase (eNOS) with a subsequent enhancement of NO generation [48][49][50][51].…”

“…In a rat model of pentylenetetrazole-induced seizures, luteolin pretreatment suppressed seizure induction and severity of symptoms by activating the PKA pathway [46]. In rat corpus cavernosum smooth muscle cells, the inhibitory effect of flavonoids was mediated by PDE5 inhibition, leading to increased cGMP levels [47]. In addition, flavonoid aglycones may increase the expression and activity of endothelial NO-synthase (eNOS) with a subsequent enhancement of NO generation [48][49][50][51].…”

The pharmacological effects and safety of the raw and prepared folium of Epimedium brevicornu Maxim. on improving kidney-yang deficiency syndrome and sexual dysfunction

“…This test adopted the method we have published previously (Li et al, 2022). Briefly, all samples were diluted in assay buffer which contained 100 mM MgCl 2 and 50 mM Tris-HCl (pH 8.0).…”