Discovery of (4-Aminophenyl)Nicotinic Acid Derivatives as Novel Sirt3 Inhibitors: A Structural Modification Approach

Abstract

Inhibition of SIRT3 has been promising for the treatment of cancer. In discovery of novel SIRT3 inhibitors with improved anticancer potency, structural modification was performed on the previously derived compounds. A total of 37 compounds were designed and synthesized. In the enzyme inhibitory assay, molecules D16 and D24 showed potent SIRT3 inhibitory activity and selectivity. Moreover, compounds D16 and D24 exhibited in vitro antiproliferative activities by inhibiting the growth of different leukemic cell lines and decreasing the formation of cancer cell colonies. In the cell cycle analysis, molecules D16 and D24 induced G0/G1 cell cycle arrest. Significantly, compounds D16 and D24 stimulated the differentiation of tested cells in the cellular morphological evaluation, accompanied by increasing the expression of differentiation antigen CD13 and CD14. Moreover, compound D24 exhibited in vivo anticancer activity in the nude mice model. Collectively, potent SIRT3 selective inhibitors were developed for further discovery of anticancer drugs.

Note:
Funding declaration: This work was supported by the Natural Science Foundation of China (22171166, 22235001 and 22211530417).

Conflict of Interests: No potential conflict of interest was reported by the authors.

Ethical Approval: The animal study was reviewed and approved by Animal Care and Use Committee of Shandong Second Medical University (ACUC-SDSMU, approval ID: 2024SDL258).

Keywords: SIRT3, inhibitor, structural modification, Anticancer, differentiation