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Article

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

1
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland
2
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, 53-114 Wrocław, Poland
3
Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland
4
Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Carlos Alberto Manssour Fraga
Pharmaceuticals 2021, 14(9), 851; https://doi.org/10.3390/ph14090851
Received: 28 July 2021 / Revised: 19 August 2021 / Accepted: 23 August 2021 / Published: 26 August 2021
(This article belongs to the Special Issue Drug Insight: Histone Deacetylase (HDAC) Inhibitors)
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. View Full-Text
Keywords: Vorinostat; histone deacetylase; HDAC inhibitors; dibenzodiazocines; hydroxamic acid; selectivity Vorinostat; histone deacetylase; HDAC inhibitors; dibenzodiazocines; hydroxamic acid; selectivity
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MDPI and ACS Style

Bieszczad, B.; Garbicz, D.; Świtalska, M.; Dudek, M.K.; Warszycki, D.; Wietrzyk, J.; Grzesiuk, E.; Mieczkowski, A. Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues. Pharmaceuticals 2021, 14, 851. https://doi.org/10.3390/ph14090851

AMA Style

Bieszczad B, Garbicz D, Świtalska M, Dudek MK, Warszycki D, Wietrzyk J, Grzesiuk E, Mieczkowski A. Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues. Pharmaceuticals. 2021; 14(9):851. https://doi.org/10.3390/ph14090851

Chicago/Turabian Style

Bieszczad, Bartosz, Damian Garbicz, Marta Świtalska, Marta K. Dudek, Dawid Warszycki, Joanna Wietrzyk, Elżbieta Grzesiuk, and Adam Mieczkowski. 2021. "Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues" Pharmaceuticals 14, no. 9: 851. https://doi.org/10.3390/ph14090851

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