6533b831fe1ef96bd129911c
RESEARCH PRODUCT
The new 5- or 6-azapyrimidine and cyanuric acid derivatives of L-ascorbic acid bearing the free C-5 hydroxy or C-4 amino group at the ethylenic spacer: CD-spectral absolute configuration determination and biological activity evaluations
Mario CetinaMario CetinaKari RissanenM. Stipković BabićM. KošutićKrešimir PavelićMirela SedićS. Kraljević PavelićKarlo WittineMladen MintasA. Tomljenović Paravićsubject
Double bondStereochemistryAscorbic AcidCrystallography X-Ray010402 general chemistry01 natural sciencesCell LineCytosineInhibitory Concentration 50Structure-Activity Relationship03 medical and health scienceschemistry.chemical_compound0302 clinical medicineDrug DiscoveryHumansUracilta116Pharmacologychemistry.chemical_classificationTriazinespyrimidine and cyanuric acid derivatives; L-ascorbic acid; circular dichroism; cytostatic activity evaluation; X-ray diffractionOrganic ChemistryAbsolute configurationHydrogen BondingStereoisomerismUracilBiological activityHep G2 CellsGeneral MedicineFibroblastsCytostatic AgentsAscorbic acidpyrimidine and cyanuric acid derivatives ; L-ascorbic acid ; circular dichroism ; cytostatic activity evaluation ; X-ray diffraction ; cell cycle analysis0104 chemical sciences3. Good healthchemistry030220 oncology & carcinogenesisS Phase Cell Cycle CheckpointsMCF-7 CellsCyanuric acidCytosineLactoneHeLa Cellsdescription
Abstract We report on the synthesis of the novel types of cytosine and 5-azacytosine (1–9), uracil and 6-azauracil (13–18) and cyanuric acid (19–22) derivatives of l -ascorbic acid, and on their cytostatic activity evaluation in human malignant tumour cell lines vs. their cytotoxic effects on human normal fibroblasts (WI38). The CD spectra analysis revealed that cytosine (5 and 6), uracil (14–16), 6-azauracil (17) and cyanuric acid (21) derivatives of l -ascorbic acid bearing free amino group at ethylenic spacer existed as a racemic mixture of enantiomers, whereas L-ascorbic derivatives containing the C-5 substituted hydroxy group at the ethylenic spacer were obtained in (4R, 5S) enantiomeric form. The stereochemistry of 6-azauracil derivative of l -ascorbic acid (13) was confirmed by X-ray crystal structure analysis. The molecules are self-assembled by one N–H⋯O hydrogen bond, two C–H⋯O hydrogen bonds and two C–H⋯π interactions into three-dimensional framework. Cytostatic activity evaluation indicated that compounds did not show distinctive antiproliferative effects on tested cell line panel. However, the cytosine derivative of l -ascorbic acid (1) containing the C4-C5 double bond conjugated with the lactone moiety produced rather marked growth inhibitory effect on hepatocellular carcinoma (HepG2), metastatic breast epithelial carcinoma (MCF-7) and cervical carcinoma (HeLa) cell lines at micromolar concentrations, but also exerted strong cytostatic effect on WI38. 5-Azacytosine derivative of l -ascorbic acid (2) with a double bond at the C4–C5 conjugated with the lactone moiety displayed potent antitumour activity against tested tumour cell lines with meanIC50 values ranging from 0.92 to 5.91 μM. However, this compound also exhibited pronounced cytotoxicity towards WI38. Flow cytometric analysis of the cell cycle revealed that compound 2 triggers S phase arrest, which clearly demonstrates its interference with DNA replication, a key event of cell proliferation. Marked anticancer efficacy of compound 2 supports further in vivo investigation into its possible clinical utility.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2011-01-01 |