Novel Vorinostat Analogues with Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity Against Leukemias and Lymphomas

Abstract

Histone deacetylase (HDAC) inhibitors are class of drugs used in the cancer treatment. Here, we developed a library of 19 analogues of Vorinostat, an HDAC inhibitor used in lymphomas treatment. In Vorinostat, we replaced the hydrophobic phenyl group with various tricyclic ‘caps’ possessing a central, eight-membered, heterocyclic ring, and investigated the HDAC activity and cytotoxic effect on the cancer and normal cell lines. We found that three out of the 19 compounds, based on dibenzo[b,f]azocin-6(5H)-one, 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one and benzo[b]naphtho[2,3-f][1,5]diazocine-6,14(5H,13H)-dione scaffolds, showed better HDACs inhibition than the referenced Vorinostat. In leukemic cell line MV4-11 and in lymphoma cell line – Daudi three compounds showed lower IC50 values than Vorinostat. These compounds had higher activity and selectivity against MV4-11 and Daudi cell lines than reference Vorinostat. We also observed a strong correlation between HDACs inhibition and the cytotoxic effect. Cell lines derived from solid tumors: A549 (lung carcinoma) and MCF-7 (breast adenocarcinoma) as well as reference Balb/3T3 (normal murine fibroblasts) were less susceptible to compounds tested. Developed derivatives show superior properties than Vorinostat, thus they are applicable as selective agents for leukemia and lymphoma treatment.