{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:27:44Z","timestamp":1792672064905,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2024,12,2]],"date-time":"2024-12-02T00:00:00Z","timestamp":1733097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The huge amount of citrus peel produced worldwide represents an economic burden for society. However, this agricultural by-product is a rich source of natural molecules, potentially endowed with interesting pharmacological activities. In this regard, we decided to investigate if the polymethoxyflavones contained in citrus peel waste could be exploited as novel vasorelaxant agents. A hydroalcoholic blond orange (Citrus sinensis) peel extract, obtained by ultrasonication, was partitioned in dichloromethane. Column chromatography allowed for the isolation of four polymethoxyflavones, namely, scutellarein tetramethyl ether, nobiletin, tangeretin, and sinensetin, identified by nuclear magnetic resonance (NMR) spectroscopy and UPLC-HRMS\/MS and confirmed by multivariate curve resolution of NMR fractional spectra. The four molecules showed interesting in vitro vasorelaxant activity, at least, in part, due to the blockade of smooth muscle CaV1.2 channels. Molecular modeling and docking analysis elucidated the binding mode of the polymethoxyflavones at the homology model of the rat CaV1.2c subunit and provided the structural basis to rationalise the highest activity of scutellarein tetramethyl ether in the set and the dramatic effect of the additional methoxy group occurring in nobiletin and sinensetin. In conclusion, citrus peel can be considered a freely available, valuable source of vasoactive compounds worthy of pharmaceutical and\/or nutraceutical exploitation.<\/jats:p>","DOI":"10.3390\/molecules29235693","type":"journal-article","created":{"date-parts":[[2024,12,3]],"date-time":"2024-12-03T10:52:30Z","timestamp":1733223150000},"page":"5693","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Bioguided Identification of Polymethoxyflavones as Novel Vascular CaV1.2 Channel Blockers from Citrus Peel"],"prefix":"10.3390","volume":"29","author":[{"given":"Anna","family":"Ramunno","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Salerno, 84084 Fisciano, SA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9243-1307","authenticated-orcid":false,"given":"Rosa Maria","family":"Vitale","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry-National Research Council (ICB-CNR), 80078 Pozzuoli, NA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6439-7575","authenticated-orcid":false,"given":"Pietro","family":"Amodeo","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry-National Research Council (ICB-CNR), 80078 Pozzuoli, NA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6950-1506","authenticated-orcid":false,"given":"Carlo","family":"Crescenzi","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, 84084 Fisciano, SA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Panti","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, University of Siena, 53100 Siena, TS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Fiorenzani","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, TS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9036-1595","authenticated-orcid":false,"given":"Michele","family":"De Luca","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5447-9497","authenticated-orcid":false,"given":"Umile Gianfranco","family":"Spizzirri","sequence":"additional","affiliation":[{"name":"Ionian Department of Law, Economics and Environment, University of Bari Aldo Moro, 74123 Taranto, TA, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donatella","family":"Restuccia","sequence":"additional","affiliation":[{"name":"Department of Management, University of Roma La Sapienza, 00161 Rome, RM, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6846-5582","authenticated-orcid":false,"given":"Francesca","family":"Aiello","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, CS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5737-8309","authenticated-orcid":false,"given":"Fabio","family":"Fusi","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, 53100 Siena, TS, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/s11101-017-9497-1","article-title":"Phytochemistry and Bioactivity of Citrus Flavonoids: A Focus on Antioxidant, Anti-Inflammatory, Anticancer and Cardiovascular Protection Activities","volume":"16","author":"Yi","year":"2017","journal-title":"Phytochem. 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