title: Synthesis and biological evaluation of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamides as pyruvate dehydrogenase kinase 1 (PDK1) inhibitors to reduce the growth of cancer cells.
abstract: 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.
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Shao-Lin
authors.initials: SL
authors.lastname: Zhang
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Hu
authors.affiliation: Faculty of Health Sciences, University of Macau, Macau, China. Electronic address: kintam@umac.mo.
authors.forename: Kin Yip
authors.initials: KY
authors.lastname: Tam
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D008928:Mitochondria / Q000187:drug effects; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase
chemical_list: D000577:Amides; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C000631429:PDK1 protein, human; D011422:Propionates; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D010088:Oxidoreductases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose
keywords: Anti-proliferation; Binding affinity; Pyruvate dehydrogenase complex; Pyruvate dehydrogenase kinase