Cytotoxicity of cinchona alkaloid organocatalysts against MES-SA and MES-SA/Dx5 multidrug-resistant uterine sarcoma cell lines. (1st August 2022)

• Record Type: Journal Article
• Authors: Pósa, Szonja Polett; Dargó, Gyula; Nagy, Sándor; Kisszékelyi, Péter; Garádi, Zsófia; Hámori, Lilla; Szakács, Gergely; Kupai, József; Tóth, Szilárd
• Is Part Of: Bioorganic & medicinal chemistry. Volume 67(2022)
• Publication Date: 2022-08-01
• Subjects: Cinchona -- Citotoxicity -- Anticancer activity -- Multidrug resistance -- P-glycoprotein inhibitors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2022.116855
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Cinchona alkaloid derivatives were synthesised from quinine and their potential anticancer activity against MES-SA and Dx5 uterine sarcoma multidrug-resistant cell lines was investigated. Abstract: 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.