title: 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.
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Fedora
authors.initials: F
authors.lastname: Grande
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy; Department of Informatics, Modeling, Electronics and Systems Engineering, University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Ortensia I
authors.initials: OI
authors.lastname: Parisi
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Roberta A
authors.initials: RA
authors.lastname: Mordocco
authors.affiliation: Department of Biology, Ecology and E.S., University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Rocca
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy. Electronic address: francesco.puoci@unical.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Puoci
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Scrivano
authors.affiliation: Department of Biology, Ecology and E.S., University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Quintieri
authors.affiliation: Department of Biology, Ecology and E.S., University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Cantafio
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ferla
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brancale
authors.affiliation: Department of Pharmaceutical and Biomedical Sciences, University of Salerno, 84084 Fisciano, SA, Italy.
authors.forename: Carmela
authors.initials: C
authors.lastname: Saturnino
authors.affiliation: Department of Biology, Ecology and E.S., University of Calabria, 87036 Arcavacata di Rende, CS, Italy. Electronic address: maria_carmela.cerra@unical.it.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Cerra
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Maria S
authors.initials: MS
authors.lastname: Sinicropi
authors.affiliation: Department of Biology, Ecology and E.S., University of Calabria, 87036 Arcavacata di Rende, CS, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Angelone
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005750:Gastric Juice / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology; D007419:Intestinal Secretions / Q000378:metabolism; D008958:Models, Molecular; D010194:Pancreatin / Q000378:metabolism; D010434:Pepsin A / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D010194:Pancreatin; D011794:Quercetin; D010434:Pepsin A
keywords: Heart; Hypertension; Nitric oxide; Quercetin