Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.
Bioorg Med Chem. 2012 Feb 15;20(4):1607-15. doi: 10.1016/j.bmc.2011.12.018. Epub 2011 Dec 27.
Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei.
醌类化合物已被开发为一类有潜力的抗癌化合物。它们被认为是双重迈克尔受体，与目标蛋白形成两个共价键。醌类化合物也被证明对寄生虫布氏锥虫具有活性，布氏锥虫是人类非洲锥虫病的病原体，但在对照筛选中，它们对哺乳动物 MRC5 细胞的选择性很小。在本文中，我们报告了对 T. brucei 的进一步醌类化合物的筛选。我们能够推导出一个 SAR，但这些化合物对 MRC5 细胞的选择性很小。为了提高选择性，我们将三聚氰胺和苯甲脒基引入醌类化合物中，因为这些部分已知通过转运蛋白选择性地集中在寄生虫中。一般来说，这些含有转运体基序的类似物显示出更高的选择性；然而，它们对 T. brucei 的效力也降低了。
