Quinazolin-4(3H)-one-Based Hydroxamic Acids: Design, Synthesis and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Article abstract of DOI:10.1002/cbdv.201800502

The present article describes the synthesis and biological activity of various series of novel hydroxamic acids incorporating quinazolin-4(3H)-ones as novel small molecules targeting histone deacetylases. Biological evaluation showed that these hydroxamic acids were potently cytotoxic against three human cancer cell lines (SW620, colon; PC-3, prostate; NCI?H23, lung). Most compounds displayed superior cytotoxicity than SAHA (suberoylanilide hydroxamic acid, Vorinostat) in term of cytotoxicity. Especially, N-hydroxy-7-(7-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5b) and N-hydroxy-7-(6-methyl-4-oxoquinazolin-3(4H)-yl)heptanamide (5c) (IC₅₀ values, 0.10–0.16 μm) were found to be approximately 30-fold more cytotoxic than SAHA (IC₅₀ values of 3.29–3.67 μm). N-Hydroxy-7-(4-oxoquinazolin-3(4H)-yl)heptanamide (5a; IC₅₀ values of 0.21–0.38 μm) was approximately 10- to 15-fold more potent than SAHA in cytotoxicity assay. These compounds also showed comparable HDAC inhibition potency with IC₅₀ values in sub-micromolar ranges. Molecular docking experiments indicated that most compounds, as represented by 5b and 5c, strictly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA.

Full text of DOI:10.1002/cbdv.201800502

Title: Quinazolin-4(3H)-one-based Hydroxamic Acids: Design,
Synthesis and Evaluation of Histone Deacetylase Inhibitory
Effects and Cytotoxicity
Authors: Doan Thanh Hieu, Duong Tien Anh, Pham The Hai, Nguyen
Thi Thuan, Le Thi Thu Huong, Eun Jae Park, A Young Ji,
Jong Soon Kang, Phan Thi Phuong Dung, Sang Bae Han,
and Nguyen-Hai Nam
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Chem. Biodiversity 10.1002/cbdv.201800502
Link to VoR: http://dx.doi.org/10.1002/cbdv.201800502

10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
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10.1002/cbdv.201800502
Chemistry & Biodiversity
This article is protected by copyright. All rights reserved.