Synthesis, Structure and In Vitro Cytotoxic Activity of Novel Cinchona—Chalcone Hybrids with 1,4-Disubstituted- and 1,5-Disubstituted 1,2,3-Triazole Linkers

Molecules

Angéla Takács¹  Eszter Lajkó¹  László Kőhidai¹  Antonio Dembo²  Antal Csámpai²  Cintia Duró²  Gitta Schlosser³  Tamás Jernei³ 

[1] Department of Genetics, Cell- and Immunobiology, Semmelweis University, Nagyvárad tér 4, H-1089 Budapest, Hungary;Department of Inorganic Chemistry, Eötvös Loránd University (ELTE), Pázmány P. sétány 1/A, H-1117 Budapest, Hungary;MTA-ELTE Research Group of Peptide Chemistry, Pázmány P. sétány 1/A, H-1117 Budapest, Hungary;

关键词: cinchona;    chalcone;    1,2,3-triazole;    hybrid compounds;    cytotoxicity;    structure-activity relationships;    cell cycle analysis;   

DOI  :  10.3390/molecules24224077

来源: DOAJ

【 摘 要 】

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.

【 授权许可】

Unknown