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

• Published in: Pharmaceuticals (Basel, Switzerland) Vol. 14; no. 9; p. 851
• Main Authors: Bieszczad, Bartosz, Garbicz, Damian, Świtalska, Marta, Dudek, Marta K, Warszycki, Dawid, Wietrzyk, Joanna, Grzesiuk, Elżbieta, Mieczkowski, Adam
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 26.08.2021; MDPI
• Subjects: Acids; Cancer therapies; Carbon; Chromatography; Chronic obstructive pulmonary disease; Cytotoxicity; dibenzodiazocines; HDAC inhibitors; histone deacetylase; hydroxamic acid; Lymphoma; Multiple myeloma; Radiation; selectivity; Vorinostat; selectivity; HDAC inhibitors; hydroxamic acid; histone deacetylase; Vorinostat; dibenzodiazocines
• ISSN: 1424-8247; 1424-8247
• DOI: 10.3390/ph14090851

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[ ]azocin-6(5 )-one, 11,12-dihydrodibenzo[ ]azocin-6(5 )-one, and benzo[ ]naphtho[2,3- ][1,5]diazocine-6,14(5 ,13 )-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 IC 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.