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

• Main Authors: Bartosz Bieszczad, Damian Garbicz, Marta Świtalska, Marta K. Dudek, Dawid Warszycki, Joanna Wietrzyk, Elżbieta Grzesiuk, Adam Mieczkowski
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Pharmaceuticals
• Subjects: Vorinostat; histone deacetylase; HDAC inhibitors; dibenzodiazocines; hydroxamic acid; selectivity
• Online Access: https://www.mdpi.com/1424-8247/14/9/851

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[<i>b,f</i>]azocin-6(5<i>H</i>)-one, 11,12-dihydrodibenzo[<i>b,f</i>]azocin-6(5<i>H</i>)-one, and benzo[<i>b</i>]naphtho[2,3-<i>f</i>][1,5]diazocine-6,14(5<i>H</i>,13<i>H</i>)-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.