Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

Abstract

The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10(-8)M÷10(-6)M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10(-10)M and 10(-8)÷10(-6)M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension.

Dissection of the Effects of Quercetin on Mouse Myocardium

“…Another study also verified in rat heart that application of quercetin resulted in positive inotropic and lusitropic effects at very low concentrations (10 À10 to 10 À8 M) and negative inotropic and lusitropic effects at higher concentrations (10 À7 and 10 À6 M) [22]. In the heart, activation of a1-adrenoceptor elicits positive inotropic response by activating the GTP-binding protein (Gq) that activates phospholipase C and increases signalling through IP 3 /Ca 2+ /PKC cascade [23].…”

“…It was observed that quercetin‐elicited positive inotropism and lusitropism was dependent on β 1 /β 2 ‐adrenoceptors and was associated with increased intracellular cAMP, while the negative inotropism and lusitropism observed at higher concentrations were dependent on α‐adrenoceptor activation . Another study also verified in rat heart that application of quercetin resulted in positive inotropic and lusitropic effects at very low concentrations (10 −10 to 10 −8 M) and negative inotropic and lusitropic effects at higher concentrations (10 −7 and 10 −6 M) . In the heart, activation of α1‐adrenoceptor elicits positive inotropic response by activating the GTP‐binding protein (Gq) that activates phospholipase C and increases signalling through IP 3 /Ca 2+ /PKC cascade .…”

Cancer chemoprevention through dietary flavonoids: what’s limiting?

“…Methyl- and hyro-sliybin derivatives have been reported to be 10-fold more potent than the parent compound, sylibin [202–205]. The introduction of hydrophobic functional groups (e.g., ethyl substitution) on the hydroxyl (OH) groups in quercetin significantly enhances its stability by preventing oxidative degradation of the hydroxyl groups [206]. Furthermore, the hydrophobic substitutions increase lipophilicity (quercetin’s clogP = 2, hydrophobic derivatives clogP = 3–12), which increases penetrability through biological membranes (bioavailability was increased from 10.7% for quercetin to 18.8% for one of its derivatives) [206].…”

“…The introduction of hydrophobic functional groups (e.g., ethyl substitution) on the hydroxyl (OH) groups in quercetin significantly enhances its stability by preventing oxidative degradation of the hydroxyl groups [206]. Furthermore, the hydrophobic substitutions increase lipophilicity (quercetin’s clogP = 2, hydrophobic derivatives clogP = 3–12), which increases penetrability through biological membranes (bioavailability was increased from 10.7% for quercetin to 18.8% for one of its derivatives) [206]. It has also been shown that blocking some groups (e.g., C3 hydroxyl and C7 hydroxyl groups) in quercetin by the introduction of the lipophilic moiety pivaloxymethyl (POM) enhances its solubility, decreases its metabolism, enhances stability (half-life increased from 10 h for quercetin to >72 h for its quercetin-POM conjugates at pH 7.4), and increases its effectiveness by preventing chemical and metabolic hydrolysis [207].…”

Synthesis of sericin-based conjugates by click chemistry: enhancement of sunitinib bioavailability and cell membrane permeation

“…The in vitro bioavailability study was carried out in a simulated gastric and intestinal environment through the previously reported method of the dialysis tubing procedure (Grande et al, 2016). The experiment is based on two successive enzymatic phases: pepsin and pancreatin digestions, which occurs in the first 2 h and in the following 4 h, respectively.…”