Synthesis and evaluation of the antiproliferative activities of derivatives of carboxyalkyl isoflavones linked to N-t-Boc-hexylenediamine

The isoflavones biochanin A (1a), genistein (1b), and daidzein (4) at concentrations >20 μM inhibit cell growth of various cancer cell lines. To enhance the antiproliferative activities of these compounds, we synthesized three analogs, 2-[3-carboxy-(6-tert-butoxycarbonylamino)-hexylamino-propyl]-7,5- dihydroxy-4′-methoxyisoflavone (3a), 2-[3-[N-[6-(tert-butoxycarbonyl)- aminohexyl]]-caboxamidopropyl]-5,7,4′-trihydroxyisoflavone (3b), and 5-{2-[3-(4-hydroxy-phenyl)-4-oxo-4H-chromen-7-yloxy]-acetylamino}-pentyl) -carbamic acid tert-butyl ester (6). When cancer cells expressing predominantly estrogen receptor mRNA of the β- relative to α-subtype were treated with 3a, 3b, or 6, DNA synthesis was inhibited in a dose-dependent manner, ranging from 15 to 3000 nmol/L, with little inhibitory effect in normal vascular smooth muscle cells. Compound 6 was the most potent one, and its antiproliferative effect in cancer cells was modulated by estrogen and by the apoptosis inhibitor Z-VADFK. When tested in vivo, compound 6 decreased tumor volume of ovarian xenografts by 50%, with no apparent toxicity. Compound 6 may be a promising agent for therapy of cancer either alone or in combination with chemotherapeutic agents.