Dichloroacetophenones targeting at pyruvate dehydrogenase kinase 1 with improved selectivity and antiproliferative activity: Synthesis and structure-activity relationships. Issue 21 (15th November 2018)

• Record Type: Journal Article
• Authors: Zhang, Shao-Lin; Yang, Zheng; Hu, Xiaohui; Tam, Kin Yip
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 21(2018)
• Page Start: 3441
• Page End: 3445
• Publication Date: 2018-11-15
• Subjects: Pyruvate dehydrogenase kinase -- Pyruvate dehydrogenase complex -- Antiproliferative activity -- Dichloroacetophenone -- Kinase inhibition; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.09.026
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: Targeting cancer metabolism via the inhibition of PDK1 is a viable anticancer approach. Dichloroacetophenone is a PDK1 inhibitor with suboptimal kinase selectivity. A series of novel dichloroacetophenones derivative was synthesized. SAR analyses identified 3 potent compounds exhibiting good PDK1 selectivity. The 3 identified compounds showed good anticancer effects in NSCLC cell lines. Abstract: Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely54, 55, and64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that54, 55, and64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that54, 55, and64 could be promising compounds for the development of potent PDK1 inhibitors.