2. Academic Validation
  3. Cytotoxicity of cinchona alkaloid organocatalysts against MES-SA and MES-SA/Dx5 multidrug-resistant uterine sarcoma cell lines

Cytotoxicity of cinchona alkaloid organocatalysts against MES-SA and MES-SA/Dx5 multidrug-resistant uterine sarcoma cell lines

  • Bioorg Med Chem. 2022 Aug 1:67:116855. doi: 10.1016/j.bmc.2022.116855.
Szonja Polett Pósa 1,  Gyula Dargó 2,  Sándor Nagy 2,  Péter Kisszékelyi 2,  Zsófia Garádi 3,  Lilla Hámori 4,  Gergely Szakács 5,  József Kupai 6,  Szilárd Tóth 7
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Organic Chemistry & Technology, Budapest University of Technology & Economics, Műegyetem rakpart 3, H-1111 Budapest, Hungary.
  • 3 Department of Pharmacognosy Semmelweis University, Üllői út. 26, H-1085 Budapest, Hungary.
  • 4 Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary.
  • 5 Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary; Institute of Cancer Research, Medical University Vienna, Vienna, Austria.
  • 6 Department of Organic Chemistry & Technology, Budapest University of Technology & Economics, Műegyetem rakpart 3, H-1111 Budapest, Hungary. Electronic address: kupai.jozsef@vbk.bme.hu.
  • 7 Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary. Electronic address: toth.szilard.enzim@ttk.hu.
PMID: 35640378 DOI: 10.1016/j.bmc.2022.116855
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.

Keywords

Anticancer activity; Cinchona; Citotoxicity; Multidrug resistance; P-glycoprotein inhibitors.

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