Gyógyszerészet, farmakogenomika, gyógyszerkutatás és tervezés, gyógyszeres kezelés
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.
