Synthesis and MAPK Kinase Inhibitiory Activities in Prostate Tumors

前列腺癌是美国男性最常见的确诊癌症。2005年，据估计， 新增确诊病例230,900例。虽然雄激素消融术是一种非常有效的姑息疗法，但所有男性 最终复发是由于转移部位存在雄激素非依赖性前列腺癌细胞。 目前还没有有效消除这些雄激素非依赖性前列腺癌细胞的治疗方法。 雄激素存活和增殖相关信号转导通路的鉴定 独立的前列腺癌细胞对合理的药物开发至关重要。在初步研究中，亚胺取代 2-氯-1，4-萘醌类化合物已被鉴定为MEK-1的选择性抑制剂。超过了 在过去的一年里，已经合成了大约75个萘醌类似物，并测试了其对一组 人前列腺癌细胞系。这些研究已经确定了某些结构-细胞毒性关系 将被用于合成更多的类似物。这些研究的目标是确定有效的细胞毒性亚胺取代基。 将分析对MEK-1和其他膜的抑制活性的挥发酚类化合物 结合的和细胞内的蛋白激酶。

Prostate cancer is the most commonly diagnosed cancer in American men. In 2005, an estimated 230,900 new cases will be diagnosed. Although androgen ablation is highly effective palliative therapy, all men eventually relapse due to the presence of androgen independent prostate cancer cells within metastatic sites. Currently there is no therapy that effectively eliminates these androgen independent prostate cancer cells. Identification of the signal transduction pathways responsible for survival and proliferation of androgen independent prostate cancer cells is critical for rational drug development. In preliminary studies, imido-substituted 2-chloro-1,4-naphthoquinones have been identified, that are selective inhibitors of Mek-1. Over the past year approximately 75 napthoquinone analogs have been synthesized and tested for cytotoxicity against a panel of human prostate cancer cell lines. These studies have identified certain structure-cytotoxicity relationships that will be exploited in synthesis of additional analogs. The goal of the studies is to identify potent cytotoxic imido-substituted napthoquinones that will be analyzed for inhibitory activity against MEK-1 and other membrane bound and intracellular protein kinases.