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Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (1), a major Amaryllidaceae alkaloid isolated from Pancratium maritimum, was derivatized. Thirty-one new compounds (2\u201332) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds 1\u201332 were evaluated as MDR reversers, through the rhodamine-123 accumulation assay by flow cytometry and chemosensitivity assays, in resistant human colon adenocarcinoma cancer cells (Colo 320), overexpressing P-glycoprotein (P-gp, ABCB1). Significant inhibition of P-gp efflux activity was observed for the di-carbamate derivatives, mainly those containing aromatic substituents, at non-cytotoxic concentrations. Compound 5, bearing a benzyl substituent, and compounds 9 and 25, with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 \u00b5M, being more active than verapamil at 10-fold higher concentration. In drug combination assays, most compounds were able to synergize doxorubicin. Moreover, some derivatives showed a selective antiproliferative effect toward resistant cells, having a collateral sensitivity effect. In the ATPase assay, selected compounds (2, 5, 9, 19, 25, and 26) were shown to behave as inhibitors.<\/jats:p>","DOI":"10.3390\/ijms24032061","type":"journal-article","created":{"date-parts":[[2023,1,20]],"date-time":"2023-01-20T06:52:41Z","timestamp":1674197561000},"page":"2061","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Lycorine Carbamate Derivatives for Reversing P-glycoprotein-Mediated Multidrug Resistance in Human Colon Adenocarcinoma Cells"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3333-7729","authenticated-orcid":false,"given":"Shirley A. R.","family":"Sancha","sequence":"first","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8638-5815","authenticated-orcid":false,"given":"Nikoletta","family":"Szemer\u00e9di","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Albert Szent-Gy\u00f6rgyi Health Center, Faculty of Medicine, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8085-0950","authenticated-orcid":false,"given":"Gabriella","family":"Spengler","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology, Albert Szent-Gy\u00f6rgyi Health Center, Faculty of Medicine, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8742-1486","authenticated-orcid":false,"given":"Maria-Jos\u00e9 U.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","unstructured":"WHO (2020). Who Report on Cancer, WHO."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Catalano, A., Iacopetta, D., Ceramella, J., Scumaci, D., Giuzio, F., Saturnino, C., Aquaro, S., Rosano, C., and Sinicropi, M.S. (2022). Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies. 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