Synthesis and evaluation of biological activities of two belinostat analogs bearing fluorine at the CAP

Abstract

Histone deacetylase enzymes are overexpressed in many types of hematologic malignancies (acute myelogenous leukemia, myelofibrosis, cutaneous T-cell lymphoma, and Hodgkin lymphoma) and their inhibition of HDACs could result in the inhibition of cell proliferation and induction of apoptosis. Thus, HDAC inhibitors are candidates of anticancer drug development. Belinostat is a histone deacetylase inhibitor which was approved by the US FDA in 2014 for the treatment of refractory T-cell lymphoma and solid tumor. This paper reported the synthesis of two belinostat analogues (including a firstly synthesized compound) by introducing fluorine atoms at the hydrophobic capping group (CAP) of belinostat. The resulted compounds were then tested by molecular docking analysis and in vitro evaluation of their antioxidant and anti-cancer activities. The new compound 8a displayed the highest anti-cancer efficacy against human breast (MCF-7) and liver (Hep-G2) cancer cell lines with EC50 values of 1.5‒4.0 μg/mL. Two compounds showed the antioxidant activity with an EC50 value of 8.30‒13.60 μg/mL. These results suggested that the synthesized belinostat analogs might have anti-cancer potential for further investigation.