Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues.

Bartosz Bieszczad,Marta Świtalska,Damian Garbicz,Dawid Warszycki,Adam Mieczkowski,Marta K Dudek,Elżbieta Grzesiuk,Joanna Wietrzyk

doi:10.3390/ph14090851

Abstract

Histone deacetylase (HDAC) inhibitors are a 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 3 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 the 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 tumours: 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 improved properties than Vorinostat, thus they could be considered as possible agents for leukemia and lymphoma treatment.

Highlights

Histone deacetylases (HDAC) are an important group of enzymes playing diverse biological roles in living cells [1–4]
Hydrophobic ‘cap’ in the Vorinostat structure could have had an impact on the optimal length of the side chain terminated with hydroxamic Since increasing the size of the hydrophobic ‘cap’ in the Vorinostat structure acid, in the first part of our research, we decided to synthesize two homologous series could have had an impact on the optimal length of the side chain terminated of compounds and used two selected tricyclic ‘caps’: 5-methyldibenzo[b,f ][1,5]diazocinewith hydroxamic (8)
The introduction of a larger tricyclic hydrophobic ‘cap’ to the structure of Vorinostat in the place of the phenyl group was beneficial for biological properties and allowed for the development of compounds with improved HDAC inhibition, stronger cytotoxic effects, and higher selectivity against leukemia and lymphoma cell lines

Summary

Introduction

Histone deacetylases (HDAC) are an important group of enzymes playing diverse biological roles in living cells [1–4]. Research efforts have been largely directed to the use of HDAC inhibitors as potential anti-cancer agents [8–13]. Other applications such as anti-inflammatory [14–19], antifibriotic [20–24], or neuroprotective effect in Huntington’s disease [25–27], Alzheimer disease [27,28], spinal muscular atrophy [29], or Friedreich’s ataxia were studied [30]. HDAC inhibitors were postulated as possible therapeutic agents in asthma and chronic obstructive pulmonary disease (COPD) [31], methamphetamine addiction [32], heart failure [33–35], diabetes [36,37], depression [38], or suppression of aging processes [39].

Methods

Results

Conclusion