Structure-activity studies of the binding of the flavonoid scaffold to DNA.
BACKGROUND
Flavonoids have been shown to have a wide variety of biological activities and proven to be good scaffolds for the design of DNA-binding agents as anticancer therapeutics.


METHODS
In structure-activity relationship studies, flavonoid derivatives were designed and synthesised through various organic synthesis protocols, resulting in novel or previously described molecules. These were studied by UV-Vis absorbance and fluorescence spectroscopy as well as competition dialysis for their binding to DNA isoforms. Their cytotoxic potential was assessed using MTS assays on MCF-7 breast cancer and CCRFCEM leukaemia cell lines.


CONCLUSIONS
Introduction of moieties such as chloride, nitrogen, acetoxy and methoxy groups did not help to improve binding affinity, but introduction of tertiary amines improved the binding 1,000-fold due to an improved interaction of the compound with the nucleic acid; replacement of oxygen by sulphur increased the binding 7-fold, possibly because sulphur being less electronegative than oxygen would allow the electrons of the molecule to interact more strongly with the nucleic acid. Inhibition of growth by 50% (IG(50)) values were moderate in breast and leukaemia cancer cell lines possibly due to the flavonoids interacting with other cellular components besides the nucleic acids.
Ragazzon
Patricia A
PA
Department of Chemistry and Analytical Sciences, The Open University, Milton Keynes, MK7 6AA, U.K.
Iley
Jim
J
Missailidis
Sotiris
S
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D020552:Comet Assay; D004247:DNA / Q000737:chemistry* / Q000378:metabolism*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009690:Nucleic Acid Conformation; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D005419:Flavonoids; D004247:DNA