Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000, USA.
Bioconjug Chem. 2012 Apr 18;23(4):785-95. doi: 10.1021/bc200645n. Epub 2012 Apr 4.
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 11β-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(-)-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.
作为开发乳腺癌特异性治疗剂计划的一部分，我们合成了一种缀合试剂，它是甾体抗雌激素和强效细胞毒素阿霉素的缀合物。在这项工作中，我们采用模块化组装方法制备了一种新型的 11β-取代甾体抗雌激素，其功能化有叠氮四乙二醇部分，可与互补的阿霉素苯甲酰腙功能化有炔丙基四乙二醇部分偶联。Huisgen [3 + 2]环加成化学得到了最终的杂化物，评估了其在 ER(+)-MCF-7 和 ER(-)-MDA-MB-231 乳腺癌细胞系中的选择性摄取和细胞毒性。结果表明，在杂种化合物中存在抗雌激素成分对于 ER(+)-MCF-7 人乳腺癌细胞的选择性和细胞毒性至关重要，因为杂种比阿霉素抑制细胞增殖和促进细胞死亡的效力高约 70 倍。
