Design, Synthesis, and Initial Biological Evaluation of a Steroidal Anti-Estrogen鈥揇oxorubicin Bioconjugate for Targeting Estrogen Receptor-Positive Breast Cancer Cells

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• 作者：Kinh-Luan Dao ; Rupa R. Sawant ; J. Adam Hendricks ; Victoria Ronga ; Vladimir P. Torchilin ; Robert N. Hanson
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：April 18, 2012
• 年：2012
• 卷：23
• 期：4
• 页码：785-795
• 全文大小：453K
• 年卷期：v.23,no.4(April 18, 2012)
• ISSN：1520-4812

文摘

As part of our program to develop breast cancer specific therapeutic agents, we have synthesized a conjugate agent that is a conjugate of the steroidal anti-estrogen and the potent cytotoxin doxorubicin. In this effort, we employed a modular assembly approach to prepare a novel 11尾-substituted steroidal anti-estrogen functionalized with an azido-tetraethylene glycol moiety, which could be coupled to a complementary doxorubicin benzoyl hydrazone functionalized with a propargyl tetraethylene glycol moiety. Huisgen [3 + 2] cycloaddition chemistry gave the final hybrid that was evaluated for selective uptake and cytotoxicity in ER(+)-MCF-7 and ER(鈭?-MDA-MB-231 breast cancer cell lines. The results demonstrated that the presence of the anti-estrogenic component in the hybrid compound was critical for selectivity and cytotoxicity in ER(+)-MCF-7 human breast cancer cells as the hybrid was 70-fold more potent than doxorubicin in inhibition of cell proliferation and promoting cell death.