Intensive research on genistein biomedical properties prompted many researchers to synthesize its derivatives with intention to improve their stability, activity and bioavailability. Our previous study revealed very promising properties of unsaturated sugar substituted genistein derivatives. The purpose of this study was to synthesize and screen in vitro the library of their analogues for antiproliferative properties and stability in water solutions and in culture media. We have compared the activity and stability of genistein derivatives which contain a substituent at C-7 or C-4’ position, connected with a molecule of genistein by O-glycosidic bond. We have also compared the stability of C-7 substituted analogues differing with the type of the glycosidic bond: O-glycosides vs. C-glycosides.

Cytotoxicity of the analogues of genistein was assessed by MTT assay after 72-hour incubation of HCT116 and DU 145 cell lines with the tested compounds. The influence of selected compounds on the cell cycle was determined using flow cytometer. Comet assay was used to check whether the derivatives cause DNA damage. LC / MSⁿ was used to determine the stability of the compounds in after-culture medium. Isoflavones in the medium were separated using isocratic methods and detected by positive ionization mode and using electrospray ionization interface (ESI). 

On the base of the obtained results the influence of the position of a substitution of genistein on the antiproliferative activity and inhibition of cell cycle was determined. Genistein analogues which contained a sugar substituent at C-7 position showed the ability to inhibit the cell cycle in G2 and M phase. Compounds in which the sugar was attached at C-4' position caused the inhibition of the cell cycle in G1 phase. Compounds of Ram-X ' series and Gen-5' did not cause either single or double strand brakes in DNA structure. In contrast, derivatives of Ram-C series increased the level of DNA damage in relation to the untreated control.

The stability of compounds depended on the type of glycosidic bond connecting the substituent with a molecule of genistein. Derivatives which contained C-glycosidic bond had higher stability in comparison to compounds containing O-glycosidic bond. The type of a glycosidic bond did not influence the biological activity of compounds. Glycoconjugates of Ram-C series showed similar ability to inhibit the cell proliferation as their O-glycosidic analogues. 

Acknowledgements

Research studies part-financed by the European Regional Development Fund (POIG. 01.01.02-14-102/09)

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