Department of Organic Chemistry & Technology, Budapest University of Technology & Economics, Műegyetem rakpart 3, H-1111 Budapest, Hungary; Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.
Department of Organic Chemistry & Technology, Budapest University of Technology & Economics, Műegyetem rakpart 3, H-1111 Budapest, Hungary.
Bioorg Med Chem. 2022 Aug 1;67:116855. doi: 10.1016/j.bmc.2022.116855. Epub 2022 May 26.
Since the first application of natural quinine as an anti-malarial drug, cinchona alkaloids and their derivatives have been exhaustively studied for their biological activity. In our work, we tested 13 cinchona alkaloid organocatalysts, synthesised from quinine. These derivatives were screened against MES-SA and Dx5 uterine sarcoma cell lines for in vitro anticancer activity and to investigate their potential to overcome P-glycoprotein (P-gp) mediated multidrug resistance (MDR). Decorating quinine with hydrogen-bond donor units, such as thiourea and (thio)squaramide, resulted in decreased half-maximal growth inhibition values on both cell lines (1.3-21 µM) compared to quinine and other cinchona alcohols (47-111 µM). Further cytotoxicity studies conducted in the presence of the P-gp inhibitor tariquidar indicated that several analogues, especially cinchona amines and squaramides, but not thiosquaramide, were expelled from MDR cells by P-gp. Similarly to the established P-gp inhibitor quinine, 6 cinchona analogues were shown to inhibit calcein-AM efflux. Interestingly, quinine and didehydroquinine exhibited a marginally increased toxicity against the multidrug resistant Dx5 cells. Collateral sensitivity of the MDR cell line was more pronounced when the cinchona thiosquaramide was complexed with Cu(II) acetate. Based on the results, cinchona derivatives are good anticancer candidates for further drug development.
自天然奎宁首次被用作抗疟药物以来，人们对金鸡纳生物碱及其衍生物进行了广泛的研究，以探索其生物活性。在我们的工作中，测试了 13 种由奎宁合成的金鸡纳生物碱有机催化剂。这些衍生物针对 MES-SA 和 Dx5 子宫肉瘤细胞系进行了体外抗癌活性筛选，并研究了它们克服 P-糖蛋白（P-gp）介导的多药耐药（MDR）的潜力。在奎宁上修饰氢键供体单元，如硫脲和（硫代）琥酰胺，会导致对两种细胞系的半最大生长抑制值降低（1.3-21 μM），与奎宁和其他金鸡纳醇相比（47-111 μM）。在 P-gp 抑制剂他利喹啶存在的情况下进行的进一步细胞毒性研究表明，几种类似物，特别是金鸡纳胺和琥酰胺，但不是硫代琥酰胺，可被 P-gp 从 MDR 细胞中排出。与已建立的 P-gp 抑制剂奎宁一样，6 种金鸡纳类似物被证明可抑制 calcein-AM 外排。有趣的是，奎宁和去氢奎宁对多药耐药的 Dx5 细胞表现出轻微增加的毒性。当金鸡纳硫代琥酰胺与醋酸铜（II）络合时，MDR 细胞系的交叉敏感性更为明显。基于这些结果，金鸡纳衍生物是进一步药物开发的良好抗癌候选物。
