Lev-Goldman Vered, Mester Brenda, Ben-Aroya Nurit, Koch Yitzhak, Weiner Lev, Fridkin Mati
Department of Organic Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Bioconjug Chem. 2006 Jul-Aug;17(4):1008-16. doi: 10.1021/bc050293r.
In an attempt to develop efficient chemotherapeutic agents targeted at malignant cells that express receptors, we synthesized five new emodin derivatives and their gonadotropin-releasing hormone (GnRH) conjugates to be used as potential photoactive conjugates. Emodin was modified at its hydroxy groups and included different spacers for conjugation of the peptide. We used electron spin resonance (ESR) and spin trapping techniques to study the light-stimulated redox properties of the emodin derivatives and their GnRH conjugates. Upon irradiation, all new emodin derivatives and their conjugates stimulated the formation of singlet oxygen, that is, (1)O(2), and oxygen radicals, that is, O(2)(-)() and OH(). However, substantial differences were found between the tested derivatives as to the efficacy of reactive oxygen species (ROS) production. Because of its superior ROS production properties, [d-Lys(6)(MeoEmo)]GnRH was selected as a leading conjugate. En-route to evaluate its targeting capacity, this potentially cytotoxic conjugate was tested in vitro to determine its hormonal activity and binding affinity to GnRH receptors.
为了开发针对表达受体的恶性细胞的高效化疗药物，我们合成了五种新的大黄素衍生物及其促性腺激素释放激素（GnRH）缀合物，用作潜在的光活性缀合物。大黄素在其羟基处进行了修饰，并包含用于肽缀合的不同间隔基团。我们使用电子自旋共振（ESR）和自旋捕获技术来研究大黄素衍生物及其GnRH缀合物的光刺激氧化还原性质。照射后，所有新的大黄素衍生物及其缀合物都刺激了单线态氧即(1)O(2)和氧自由基即O(2)(-)()和OH()的形成。然而，在所测试的衍生物之间，关于活性氧（ROS）产生的效率发现了显著差异。由于其优越的ROS产生特性，[d-Lys(6)(MeoEmo)]GnRH被选为主要缀合物。在评估其靶向能力的过程中，这种潜在的细胞毒性缀合物在体外进行了测试，以确定其激素活性和与GnRH受体的结合亲和力。
