Use of fisetin derivatives modified with a triphenylphosphonium group for reducing the activity of histone deacetylases (HDACs) and sirtuins in human cells cultured in vitro

Abstract

The subject of the application is the use of fisetin derivatives modified with a triphenylphosphonium group to reduce the activity of histone deacetylases (HDACs) and sirtuins in human cells cultured in vitro, which may find application in medicine. In particular, the use of concentrations not exceeding 5 µM of fisetin conjugated with a cationic triphenylphosphonium group, i.e.4-((7-acetoxy-2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-4-oxo-4H-chromen-3-yl)oxy)butyl) triphenylphosphonium iodide or (4-((3,5-diacetoxy-2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-4-oxo-4H-chromen-7-yl)oxy)butyl) triphenylphosphonium iodide leads to a decrease in the activity of histone deacetylases (HDACs) and sirtuins in proliferating triple-negative epithelial breast cancer cells characterized by mutations in the following genes: VCAM1, CD46, ZNF695, MMP8, FDX1, GPR19, RASAL1, CAMKK2, ANKLE2, ZMYM5, MAP1A, WDR24, SOX8, TPSG1, ANKS3, TXNDC11, ZNF785, RUSF1, ADGRG3, CES2, UTP4, ADAMTS18, SMG6, TP53, MY019, FAAP100, COLEC12, HMG20B, MUC16, CLOCK, PDGFRB, RUNX2, CYP3A4, MT-ND1, MT-ND3, MT-ND5, MT-ND6, MT-CYB. Additionally, the use of concentrations not exceeding 5 µM of fisetin conjugated with a cationic triphenylphosphonium group, i.e.4-((7-acetoxy-2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-4-oxo-4H-chromen-3-yl)oxy)butyl) triphenylphosphonium iodide or (4-((3,5-diacetoxy-2-(2,2-diphenylbenzo[d][1,3]dioxol-5-yl)-4-oxo-4H-chromen-7-yl)oxy)butyl) triphenylphosphonium iodide leads to a 19% to 5% decrease in the activity of histone deacetylases (HDACs) and sirtuins in cells previously induced by doxorubicin.