Faculty of Health Sciences, University of Macau, Macau, China.
Faculty of Health Sciences, University of Macau, Macau, China.
Eur J Pharm Sci. 2017 Dec 15;110:87-92. doi: 10.1016/j.ejps.2017.03.030. Epub 2017 Mar 24.
Most cancer cells exhibit a high rate of glycolysis and reduced capacity in mitochondrial oxidative phosphorylation. The expression of pyruvate dehydrogenase kinases (PDKs) was found to be increased in many cancer cells. Inhibition of PDKs increases the oxidative phosphorylation of glucose, which may disrupt the balance between the demand and supply of oxygen in cancer cell, thus leading to cell death. Several reports suggested that compounds containing (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide group could inhibit PDKs in pyruvate dehydrogenase primary enzymatic assay. However, none of them were capable of reducing the growth of cancer cells. Herein, we report the synthesis and biological evaluation of some novel PDK1 inhibitors containing the (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide warhead. Excitingly, these novel PDK1 inhibitors exhibited good potency to reduce the growth of cancer cells. We have demonstrated that these compounds could physically associate with PDK1 and activate pyruvate dehydrogenase in low micromolar levels.
大多数癌细胞表现出高糖酵解率和减少的线粒体氧化磷酸化能力。在许多癌细胞中发现丙酮酸脱氢酶激酶 (PDK) 的表达增加。PDK 的抑制增加了葡萄糖的氧化磷酸化,这可能破坏癌细胞中氧气的需求和供应之间的平衡,从而导致细胞死亡。有几项报告表明,含有 (R)-3,3,3-三氟-2-羟基-2-甲基丙酰胺基团的化合物可以在丙酮酸脱氢酶的初步酶测定中抑制 PDK。然而,它们都不能减少癌细胞的生长。在此,我们报告了一些含有 (R)-3,3,3-三氟-2-羟基-2-甲基丙酰胺弹头的新型 PDK1 抑制剂的合成和生物学评价。令人兴奋的是,这些新型 PDK1 抑制剂表现出良好的抑制癌细胞生长的活性。我们已经证明这些化合物可以在低微摩尔水平上与 PDK1 物理结合并激活丙酮酸脱氢酶。