{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T08:58:33Z","timestamp":1762073913107,"version":"build-2065373602"},"reference-count":31,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PRIN 2017 research project \u201cNovel anticancer agents endowed with multi-targeting mechanism of action\u201d","award":["201744BN5T"],"award-info":[{"award-number":["201744BN5T"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The insurgence of drug resistance in treating Multiple Myeloma (MM) still represents a major hamper in finding effective treatments, although over the past decades new classes of drugs, such as proteasome inhibitors and immunomodulatory drugs, have been discovered. Recently, our research team, within a Nature-Aided Drug Discovery project, isolated from Hibiscus Sabdariffa L. calyces the secondary metabolite called Hib-ester which possesses antiproliferative properties against human multiple myeloma RPMI 8226 cells, reduces migration and cell invasion and inhibits proteasome without neurotoxic effects. In the present study, we explored the chemical spaces of the hit compound Hib-ester. We explored the structure-activity relationships (SAR), and we optimized the scaffold through sequentially modifying Hib-ester subunits. Compound screening was performed based on cytotoxicity against the RPMI 8226 cells to assess the potential efficacy toward human MM. The ability of the most effective molecules to inhibit the proteasome was evaluated and the binding mode of the most promising compounds in the proteasome chymotrypsin binding pocket was deciphered through molecular modeling simulations. Compounds 13 and 14 are more potent than Hib-ester, demonstrating that our strategy was suitable for the identification of a novel chemotype for developing possible drug candidates and hopefully widening the drug armamentarium against MM.<\/jats:p>","DOI":"10.3390\/ijms232113061","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T20:37:58Z","timestamp":1666903078000},"page":"13061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["From Nature to Synthetic Compounds: Novel 1(N),2,3 Trisubstituted-5-oxopyrrolidines Targeting Multiple Myeloma Cells"],"prefix":"10.3390","volume":"23","author":[{"given":"Roberta","family":"Listro","sequence":"first","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alessio","family":"Malacrida","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4874-2946","authenticated-orcid":false,"given":"Francesca Alessandra","family":"Ambrosio","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1008-5736","authenticated-orcid":false,"given":"Giacomo","family":"Rossino","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Di Giacomo","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Cavalloro","sequence":"additional","affiliation":[{"name":"Department of Earth and Environmental Sciences, University of Pavia, Via Sant\u2019Epifanio 14, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Garbagnoli","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0382-7479","authenticated-orcid":false,"given":"Pasquale","family":"Linciano","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2458-3728","authenticated-orcid":false,"given":"Daniela","family":"Rossi","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4128-2406","authenticated-orcid":false,"given":"Guido","family":"Cavaletti","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-9479","authenticated-orcid":false,"given":"Giosu\u00e8","family":"Costa","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Alcaro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"},{"name":"Net4Science Academic Spin-Off, University \u201cMagna Gr\u00e6cia\u201d of Catanzaro, Campus \u201cS. Venuta\u201d, Viale Europa, 88100 Catanzaro, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6971-5827","authenticated-orcid":false,"given":"Mariarosaria","family":"Miloso","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, Milan Center for Neuroscience, University of Milan Bicocca, Via Cadore 48, 20900 Monza, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2954-7558","authenticated-orcid":false,"given":"Simona","family":"Collina","sequence":"additional","affiliation":[{"name":"Department of Drug Sciences, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"C21","DOI":"10.12968\/hmed.2017.78.2.C21","article-title":"Multiple Myeloma","volume":"78","author":"Chavda","year":"2017","journal-title":"Br. 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