Development of dichloroacetamide pyrimidines as pyruvate dehydrogenase kinase inhibitors to reduce cancer cell growth: synthesis and biological evaluation. Issue 82 (18th August 2016)

• Record Type: Journal Article
• Authors: Zhang, Shao-Lin; Zhang, Wen; Xiao, Qingpin; Yang, Zheng; Hu, Xiaohui; Wei, Zhiyi; Tam, Kin Yip
• Is Part Of: RSC advances. Volume 6:Issue 82(2016)
• Page Start: 78762
• Page End: 78767
• Publication Date: 2016-08-18
• Subjects: Chemistry -- Periodicals; 540.5
• DOI: 10.1039/c6ra14060b
• Languages: English
• ISSNs: 2046-2069

Abstract

Abstract : The synthesis and biological assays were described herein to firstly identify a novel PDK1 inhibitor. Abstract : Pyruvate dehydrogenases kinases (PDKs) have recently emerged as an attractive target for anticancer treatment. Herein, we report the synthesis and biological evaluation of novel PDK1 inhibitors as anticancer agents. Of the newly synthesized compounds, N -(4, 6-bis(4-(2-hydroxyacetyl)piperazin-1-yl)-2-methylpyrimidin-5-yl)-2, 2-dichloroacetamide (40 ) is found to inhibit the growth of SF188 cancer cells with an IC50 value of 8.21 µM. Isothermal titration calorimetry (ITC) experiments reveal that compound40 directly binds to PDK1 with a K d value of 14.7 µM. Compound40 inhibits PDK1 activity by 72.5% at a concentration of 40 µ, meaning it could be a useful compound to explore the pharmacology of PDK1.