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

Tamás Jernei, Cintia Duró, Antonio Dembo, Eszter Lajkó, Angéla Takács, László Kohidai, Gitta Schlosser, VAntal Csámpai

Research output: Contribution to journalArticle

Abstract

Abstract: 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.

Original languageEnglish
Article numbermolecules24224077
JournalMolecules
Volume24
Issue number22
DOIs
Publication statusPublished - Nov 11 2019

Fingerprint

Cinchona
Chalcone
Quinidine
Triazoles
Cells
Chalcones
Quinine
Alkynes
Ruthenium
Azides
Cyclization
synthesis
Cytotoxicity
Discrete Fourier transforms
Transition metals
Conformations
Copper
Assays
fragments
G2 Phase

Keywords

  • 1,2,3-triazole
  • Cell cycle analysis
  • Chalcone
  • Cinchona
  • Cytotoxicity
  • Hybrid compounds
  • Structure-activity relationships

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

Cite this

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. / Jernei, Tamás; Duró, Cintia; Dembo, Antonio; Lajkó, Eszter; Takács, Angéla; Kohidai, László; Schlosser, Gitta; Csámpai, VAntal.

In: Molecules, Vol. 24, No. 22, molecules24224077, 11.11.2019.

Research output: Contribution to journalArticle

Jernei, Tamás ; Duró, Cintia ; Dembo, Antonio ; Lajkó, Eszter ; Takács, Angéla ; Kohidai, László ; Schlosser, Gitta ; Csámpai, VAntal. / 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. In: Molecules. 2019 ; Vol. 24, No. 22.
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AU - Jernei, Tamás

AU - Duró, Cintia

AU - Dembo, Antonio

AU - Lajkó, Eszter

AU - Takács, Angéla

AU - Kohidai, László

AU - Schlosser, Gitta

AU - Csámpai, VAntal

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N2 - Abstract: 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.

AB - Abstract: 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.

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KW - Cinchona

KW - Cytotoxicity

KW - Hybrid compounds

KW - Structure-activity relationships

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