Genistein, the principal isoflavone constituent of soybean, attracts much attention as a natural molecule with significant affinity towards targets of potential medicinal interest, but also as a food supplement or prospective chemopreventive agent. Since its physicochemical properties are considered suboptimal for drug development, much effort has been invested in designing its analogs and conjugates in hope to obtain compounds with improved efficacy and selectivity. The aim of this article is to summarize current knowledge about the properties of synthetic genistein derivatives and to discuss possible clinical application of selected novel compounds. Some basic information concerning chemical reactivity of genistein, relevant to the synthesis of its derivatives, is also presented.
Our previous studies on antiproliferative properties of genistein derivatives substituted at C7 hydroxyl group of the ring A revealed some compounds with antimitotic properties. The aim of this work was to synthesize their analogues substituted at the 4′-position of the ring B in genistein and to define their antiproliferative mechanism of action in selected cancer cell linesin vitro. C4′-substituted glycoconjugates were obtained in a three-step procedure: (1) alkylation with anω-bromoester; (2) deacylation; (3) Ferrier-type rearrangement glycosylation with acylated glycals. Biological effects including antiproliferative effects of the compounds, cell cycle, DNA lesions (ATM activation, H2A.X phosphorylation, and micronuclei formation), and autophagy were studied in human cancer cell lines. Some of the tested derivatives potently inhibited cell proliferation. The presence of a substituent at the 4′-position of the ring B in genistein correlated to a p53-independent G1 cell-cycle arrest. The derivatives substituted at C4′ did not induce DNA lesions and appeared to be nongenotoxic. The tested compounds induced autophagy and caused remarkable decrease of cell volume.
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