In:
Chemistry & Biodiversity, Wiley, Vol. 15, No. 6 ( 2018-06)
Abstract:
In our search for novel histone deacetylases inhibitors, we have designed and synthesized a series of novel hydroxamic acids and N ‐hydroxybenzamides incorporating quinazoline heterocycles ( 4a – 4i , 6a – 6i ). Bioevaluation showed that these quinazoline‐based hydroxamic acids and N ‐hydroxybenzamides were potently cytotoxic against three human cancer cell lines ( SW 620, colon; PC ‐3, prostate; NCI ‐H23, lung). In term of cytotoxicity, several compounds, e.g ., 4g , 4c , 4g – 4i , 6c , and 6h , displayed from 5‐ up to 10‐fold higher potency than SAHA (suberoylanilidehydroxamic acid, vorinostat). The compounds were also generally comparable to SAHA in inhibiting HDAC s with IC 50 values in sub‐micromolar range. Some compounds, e.g ., 4g , 6c , 6e , and 6h , were even more potent HDAC inhibitors compared to SAHA in HeLa extract assay. Docking studies demonstrated that the compounds tightly bound to HDAC 2 at the active binding site with binding affinities higher than that of SAHA . Detailed investigation on the estimation of absorption, distribution, metabolism, excretion, and toxicity ( ADMET ) suggested that compounds 4g , 6c , and 6g , while showing potent HDAC 2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.
Type of Medium:
Online Resource
ISSN:
1612-1872
,
1612-1880
DOI:
10.1002/cbdv.201800027
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2139001-0
SSG:
12
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