Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors

Qian Hui; Xueming Li; Wenli Fan; Congying Gao; Lin Zhang; Hongyu Qin; Liuya Wei; Lei Zhang

doi:10.3389/fchem.2022.880067

Discovery of 2-(4-Acrylamidophenyl)-Quinoline-4-Carboxylic Acid Derivatives as Potent SIRT3 Inhibitors

Front Chem. 2022 Mar 30:10:880067. doi: 10.3389/fchem.2022.880067. eCollection 2022.

Authors

Qian Hui¹, Xueming Li², Wenli Fan¹, Congying Gao², Lin Zhang¹, Hongyu Qin¹, Liuya Wei², Lei Zhang¹

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China.
² Department of Inorganic Chemistry, School of Pharmacy, Weifang Medical University, Weifang, China.

Abstract

In discovery of novel SIRT3 inhibitors for the treatment of cancer, a series of 2-(4-acrylamidophenyl)-quinoline-4-carboxylic acid derivatives were designed and synthesized. Among the derived compounds, molecule P6 exhibited SIRT3 inhibitory selectivity with IC₅₀ value of 7.2 µM over SIRT1 (32.6 µM) and SIRT2 (33.5 µM). molecular docking analysis revealed a specific binding pattern of P6 in the active site of SIRT3 compared with the bindings in the active site of SIRT1 and SIRT2. In the antiproliferative and colony forming assay, molecule P6 showed potent inhibitory activity against a group of MLLr leukemic cell lines. Further analysis revealed that induction of G0/G1 phase cell cycle arrest and cell differentiation, but not apoptosis, makes contributions to the anticancer effects of P6. Collectively, a potent SIRT3 inhibitor (P6) was discovered as a lead compound for the leukemic differentiation therapy.

Keywords: SIRT3; cell cycle arrest; differentiation; mixed-lineage leukemias; selective inhibitor.