Novel Oxime Synthesized from a Natural Product of Senecio nutans SCh. Bip. (Asteraceae) Enhances Vascular Relaxation in Rats by an Endothelium-Independent Mechanism

Abstract

Senecio nutans Sch. Bip. and its constituents are reported to have antihypertensive effects. We isolated metabolite–1, a natural compound from S. nutans (4-hydroxy-3-(isopenten-2-yl)-acetophenone), and synthesized novel oxime – 1 (4-hydroxy-3-(isopenten-2-yl)-acetophenoxime) to evaluate their effect on vascular reactivity. Compounds were purified (metabolite–1) or synthetized (oxime–1) and characterized using IR and NMR spectroscopy and Heteronuclear Multiple Quantum Coherence (HMQC). Using pharmacological agents such as phenylephrine (PE) and KCl (enhancing contraction), acetylcholine (ACh), L-NAME (nitric oxide (NO) and endothelial function), Bay K8644-induced CaV1.2 channel (calcium channel modulator), and isolated aortic rings in an organ bath setup, the possible mechanisms of vascular action were determined. Pre-incubation of aortic rings with 10−5 M oxime–1 significantly (p < 0.001) decreased the contractile response to 30 mM KCl. EC50 to KCl significantly (p < 0.01) increased in the presence of oxime–1 (37.72 ± 2.10 mM) compared to that obtained under control conditions (22.37 ± 1.40 mM). Oxime–1 significantly reduced (p < 0.001) the contractile response to different concentrations of PE (10−7 to 10−5 M) by a mechanism that decreases Cav1.2-mediated Ca2+ influx from the extracellular space and reduces Ca2+ release from intracellular stores. At a submaximal concentration (10−5 M), oxime–1 caused a significant relaxation in rat aorta even without vascular endothelium or after pre-incubate the tissue with L-NAME. Oxime–1 decreases the contractile response to PE by blunting the release of Ca2+ from intracellular stores and blocking of Ca2+ influx by channels. Metabolite–1 reduces the contractile response to KCl, apparently by reducing the plasma membrane depolarization and Ca2+ influx from the extracellular space. These acetophenone derivates from S. nutans (metabolite–1 and oxime–1) cause vasorelaxation through pathways involving an increase of the endothelial NO generation or a higher bioavailability, further highlighting that structural modification of naturally occurring metabolites can enhance their intended pharmacological functions.

A new oxime synthesized from Senecio nutans SCh. Bip (chachacoma) reduces calcium influx in the vascular contractile response in rat aorta

“…Also, we found that the oxime drastically reduced the calciumdependent contractile response, suggesting that chemical modication of metabolite was successful for vascular response. 8 Here, we show for the rst time the vascular effect of 5-acetyl-6-hydroxy-2-isopropenyl-2,3-dihydrobenzofurane (Sn-I), isolated metabolite from S. nutans and its oxime (Ox-Sn-I). Also, this metabolite is also present in X. poposum.…”

“…4,5 One of them, 4-hydroxy-3-(isopenten-2-yl)-acetophenone showed a significant endothelium-dependent vasodilatation. 8…”

Effect of In Vitro Micropropagation on the Chemical, Antioxidant, and Biological Characteristics of Senecio nutans Sch. Bip., an Endemic Plant of the Atacama Desert Andean Region

“…These notable properties are associated with the different types of secondary metabolites present in the plant. Mainly, the Senecio species are rich in antioxidant compounds such as polyphenols (phenylpropanoids, 3,5-di-O-caffeoyl quinic acid, 3,4-di-O-caffeoyl quinic acid, chlorogenic acid methyl ester, caffeic acid and chlorogenic acid, tannins, and flavonoids) [ 7 , 10 ], terpenes [ 4 ], and p -hydroxyacetophenone derivates [ 11 , 12 , 13 ]. p -Hydroxyacetophenone derivates are the most abundant compounds in the aerial parts of S. nutans species [ 3 , 12 , 13 ].…”

“…Mainly, the Senecio species are rich in antioxidant compounds such as polyphenols (phenylpropanoids, 3,5-di-O-caffeoyl quinic acid, 3,4-di-O-caffeoyl quinic acid, chlorogenic acid methyl ester, caffeic acid and chlorogenic acid, tannins, and flavonoids) [ 7 , 10 ], terpenes [ 4 ], and p -hydroxyacetophenone derivates [ 11 , 12 , 13 ]. p -Hydroxyacetophenone derivates are the most abundant compounds in the aerial parts of S. nutans species [ 3 , 12 , 13 ]. Other authors found several types of p -hydroxyacetophenones in S. nutans , such as 4-hydroxy-3-(isopenten-2-yl) acetophenone, 4-hydroxy-3(3′-hydroxyisopentyl) acetophenone, and 4-hydroxy-3-(3-methyl-2-butenyl) acetophenone (AC) [ 13 ].…”

In vitro antioxidant properties and antimicrobial activity of the ethanolic extract of Senecio nutans Sch. Beep. (Asteraceae)

“…is a perennial shrub (30-60 cm high) that grows naturally in the Andean valleys of Peru and Latin America (3500-4800 m.a.s.l) (Juarez et al, 2007); in S. nutans several phytochemicals have been identified from the Andes of Peru, including sesquiterpenes (4.6%), cyclic monoterpenes (8.8% ∆ 3 -carene, 15.5% αphellandrene, 13.3-26.0% sabinene), alkylbenzenerelated monoterpenes (8.8% p-cymene), monoterpene hydrocarbons (12.2-15.1% α-terpinene, 7.5% γterpinene) (De Feo et al, 2003). In the species S. nutans, from Chile (Toconce II Region of Antofagasta) was found in addition to that described in the species from Peru (0.4% α-phellandrene, 1.1% sabinene, 1.9% p-cymene, 1.8% γ-terpinene) t-cadinol, α-cadinol, caryophyllene, p-cymenol, methyl-cinnamate, linalool, methyl-hydrocinnamate, terpinen-4-ol, α-terpineol, α-terpinene, β-pinene, trans-piperitol, and thymol (Paredes et al, 2016), sesquiterpene lactone (damsine), sesquiterpenes γ-and δ-cadinene and the spirolactone canrenone (Palacios et al, 2022); in popular medicine, these plants are used as a stomach analgesic, antiinflammatory, antipyretic, antiemetic, vasodilator, wounds, eczema, and in respiratory diseases (asthma, bronchitis, cough, colds) (Basaid et al, 2020;Lopez et al, 2018;Ouchbani et al, 2013).…”