Discovery of (4-aminophenyl)nicotinic acid derivatives as novel SIRT3 inhibitors: A structural modification approach

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 with IC50 values of 15.28 μM and 17.36 μM against SIRT3, respectively. Moreover, compounds D16 (IC 50 values of 1.37 μM, 2.39 μM, 3.87 μM, 2.68 μM and 1.02 μM against MV4–11, SEM, MM1.S, RPMI-8226 and NB4 cells) and D24 (IC 50 values of 2.08 μM, 2.72 μM, 5.74 μM, 7.32 μM and 1.26 μM against MV4–11, SEM, MM1.S, RPMI-8226 and NB4 cells) 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 with inhibitory rate of 36% compared with Cytarabine (inhibitory rate of 43%). Collectively, potent SIRT3 selective inhibitors were developed for further discovery of anticancer drugs. Potent SIRT3 selective inhibitors were discovery with cancer cell differentiation, in vitro and in vivo anticancer activities. • A series of (4-aminophenyl)nicotinic acid bearing compounds were synthesized with SIRT3 inhibitory activity and selectivity. • Molecules D16 and D24 exhibited in vitro anticancer activities in the antiproliferative assay and cell colony formation test. • Without apoptosis promoting effects, compounds D16 and D24 induced G0/G1 cell cycle arrest and triggered differentiation of MV4–11 cells. • Compound D24 exhibited in vivo anticancer activity in the nude mice model. • Potent lead compounds (such as D24 ) were discovered for further design of novel SIRT3 selective inhibitors.