Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
Department of Medical Microbiology, Albert Szent-Györgyi Health Center, Faculty of Medicine, University of Szeged, Semmelweis utca 6, 6725 Szeged, Hungary.
Int J Mol Sci. 2023 Jan 20;24(3):2061. doi: 10.3390/ijms24032061.
Multidrug resistance (MDR) is a major challenge in cancer chemotherapy. Aiming at generating a small library of anticancer compounds for overcoming MDR, lycorine (), a major Amaryllidaceae alkaloid isolated from , was derivatized. Thirty-one new compounds (-) were obtained by chemical transformation of the hydroxyl groups of lycorine into mono- and di-carbamates. Compounds - 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 , bearing a benzyl substituent, and compounds and with phenethyl moieties, were among the most active, exhibiting strong inhibition at 2 µM, 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 (, , , , , and ) were shown to behave as inhibitors.
多药耐药性（MDR）是癌症化疗的主要挑战。为了生成克服 MDR 的抗癌化合物的小文库，我们对从石蒜属植物中分离得到的主要石蒜科生物碱石蒜碱（）进行了衍生化。通过将石蒜碱的羟基化学转化为单-和二氨基甲酸酯，得到了 31 种新化合物（-）。通过流式细胞术测定罗丹明 123 积累实验和药敏实验，评估了化合物-作为多药耐药性逆转剂，用于表达 P 糖蛋白（P-gp，ABCB1）的人结肠直肠癌细胞（Colo 320）耐药株。在非细胞毒性浓度下，观察到二氨基甲酸酯衍生物对 P-gp 外排活性有显著抑制作用，主要是那些含有芳基取代基的衍生物。具有苄基取代基的化合物和含有苯乙基部分的化合物和，是最有效的化合物之一，在 2µM 时表现出强烈的抑制作用，在 10 倍更高浓度时比维拉帕米更有效。在药物联合实验中，大多数化合物能够协同增强阿霉素的作用。此外，一些衍生物对耐药细胞表现出选择性的增殖抑制作用，具有旁系敏感性效应。在 ATP 酶测定中，选定的化合物（、、、、、和）被证明是抑制剂。
