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Design, synthesis and binding mode of interaction of novel small molecule o-hydroxy benzamides as HDAC3-selective inhibitors with promising antitumor effects in 4T1-Luc breast cancer xenograft model.
- Source :
-
Bioorganic chemistry [Bioorg Chem] 2021 Dec; Vol. 117, pp. 105446. Date of Electronic Publication: 2021 Oct 22. - Publication Year :
- 2021
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Abstract
- Histone deacetylase 3 (HDAC3) is one of the most promising targets to develop anticancer therapeutics. In continuation of our quest for selective HDAC3 inhibitors, a series of small molecules having o-hydroxy benzamide as the novel zinc binding group (ZBG) has been introduced for the first time that can be able to produce good HDAC3-selectivity over other HDACs. The most promising HDAC3 inhibitors, 11a and 12b, displayed promising in vitro anticancer activities with less toxicity to normal kidney cells. These compounds significantly upregulate histone acetylation and induce apoptosis with a G2/M phase arrest in B16F10 cells. Compound 11a exhibited potent antitumor efficacy in 4T1-Luc breast cancer xenograft mouse model in female Balb/c mice. It also showed significant tumor growth suppression with no general toxicity and extended survival rates post-tumor resection. It significantly induced higher ROS generation, leading to apoptosis. No considerable toxicity was noticed in major organs isolated from the compound 11a-treated mice. Compound 11a also induced the upregulation of acH3K9, acH4K12, caspase-3 and caspase-7 as analyzed by immunoblotting with treated tumor tissue. Overall, HDAC3 selective inhibitor 11a might be a potential lead for the clinical translation as an emerging drug candidate.<br /> (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Antineoplastic Agents chemical synthesis
Antineoplastic Agents chemistry
Apoptosis drug effects
Benzamides chemical synthesis
Benzamides chemistry
Binding Sites drug effects
Cell Proliferation drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Histone Deacetylase Inhibitors chemical synthesis
Histone Deacetylase Inhibitors chemistry
Humans
Mammary Neoplasms, Experimental drug therapy
Mammary Neoplasms, Experimental metabolism
Mammary Neoplasms, Experimental pathology
Mice
Molecular Structure
Small Molecule Libraries chemical synthesis
Small Molecule Libraries chemistry
Structure-Activity Relationship
Tumor Cells, Cultured
Antineoplastic Agents pharmacology
Benzamides pharmacology
Drug Design
Histone Deacetylase Inhibitors pharmacology
Histone Deacetylases metabolism
Small Molecule Libraries pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1090-2120
- Volume :
- 117
- Database :
- MEDLINE
- Journal :
- Bioorganic chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 34717237
- Full Text :
- https://doi.org/10.1016/j.bioorg.2021.105446