Synthesis and Evaluation of the Antiproliferative Activities of Derivatives of Carboxyalkyl Isoflavones linked to N-t-Boc-hexylenediamine
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- 作者：Fortune Kohen ; Batya Gayer ; Tikva Kulik ; Veronica Frydman ; Nava Nevo ; Sara Katzburg ; Rona Limor ; Orli Sharon ; Naftali Stern ; Dalia Somjen
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：December 13, 2007
- 年：2007
- 卷：50
- 期：25
- 页码：6405 - 6410
- 全文大小：113K
- 年卷期：v.50,no.25(December 13, 2007)
- ISSN：1520-4804
文摘
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.