Object's details: Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

Provider:Repozytorium Instytutu Biochemii i Biofizyki Polskiej Akademii Nauk

Description

Title:
Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues
Creator:
Bieszczad, Bartosz;
Garbicz, Damian;
Świtalska, Marta;
Dudek, Marta K.;
Warszycki, Dawid;
Wietrzyk, Joanna;
Grzesiuk, Elzbieta;
Mieczkowski, Adam
Description:
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.
Object availability:
free access
Date:
2021.08.26
Type:
Article;
PeerReviewed
Language:
English
Format:
application/pdf
Publisher:
MDPI
Relation: http://eprints.ibb.waw.pl/2074 ;https://www.mdpi.com/1424-8247/14/9/851 ;
10.3390/ph14090851
Subject:
QD Chemistry;
RM Therapeutics. Pharmacology
Identifier: http://eprints.ibb.waw.pl/2074/1/37a.pdf ;
Bieszczad, Bartosz and Garbicz, Damian and Świtalska, Marta and Dudek, Marta K. and Warszycki, Dawid and Wietrzyk, Joanna and Grzesiuk, Elzbieta and Mieczkowski, Adam (2021) Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues. Pharmaceuticals, 14 (9). p. 851. ISSN 1424-8247
Data provider:
Repozytorium Instytutu Biochemii i Biofizyki Polskiej Akademii Nauk

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Object's details: Improved HDAC Inhibition, Stronger Cytotoxic Effect and Higher Selectivity against Leukemias and Lymphomas of Novel, Tricyclic Vorinostat Analogues

Description

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