Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups

Zhang, Qingwei; Li, Yang; Zhang, Baoyin; Lu, Bingliu; Li, Jianqi

doi:10.1016/j.bmcl.2017.09.036

Cited by 15 publications

(7 citation statements)

References 19 publications

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“…However, evaluation of the inhibitory effects against other isoforms of HDAC would be needed to fully explain for this non‐correlation between cytotoxicity and HDAC inhibition of compounds such as 4e and 6e . Interestingly, during the course of our investigation, we noted that Zhang et al . also reported a series of hydroxamic acids incorporating 4‐aminoquinazolinyl systems as cap groups, in which compounds 4a , 4c , 4g , and 4h were described to have more selective inhibition towards HDAC1, HDAc2.…”

Section: Resultsmentioning

confidence: 69%

Quinazoline‐Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Hieu

Anh

Pham-The

et al. 2018

Chemistry & Biodiversity

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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 (SW620, 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 HDACs with IC 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 HDAC2 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 HDAC2 inhibitory activity and cytotoxicity, also potentially displayed ADMET characteristics desirable to be expected as promising anticancer drug candidates.

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Section: Resultsmentioning

confidence: 69%

Quinazoline‐Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Hieu

Anh

Pham-The

et al. 2018

Chemistry & Biodiversity

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“…Further pyrazolyl-replaced analogs 2m-2r were synthesized from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 4, as depicted in Scheme 2. Compound 4 was reacted with bromo-intermediates to produce the corresponding ester derivatives 5a-5f, which were further transformed to 18 . a IC 50 values are reported as the mean of at least two independent determinations with eight concentrations each.…”

Section: Resultsmentioning

confidence: 99%

“…c-Met and HDAC enzyme inhibitory activity were conducted as described in Huang et al and Zhang et al to evaluate the final compounds using compounds crizotinib and SAHA as reference drugs. 17,18 The results are summarized in ►Tables 1-2 to 3.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

Zhang

Bao

et al. 2020

Pharmaceutical Fronts

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“…The starting material crizotinib (racemate) 1 was treated with intermediates 13a-13f or 13g-13l to give condensed ester products 3a-3l, respectively, which were treated with freshly prepared hydroxylamine methanol solution to give target compounds 2a-2l. 18 . a IC 50 values are reported as the mean of at least two independent determinations with eight concentrations each.…”

Section: Resultsmentioning

confidence: 99%

“…Abbreviations: HDAC, histone deacetylase; NT, not tested. Note: For a description of the assay conditions, please see Huang et al17 and Zhang et al18 . a IC 50 values are reported as the mean of at least two independent determinations with eight concentrations each.…”

mentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

Zhang

Bao

et al. 2020

Pharmaceutical Fronts

Self Cite

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A series of c-Met/histone deacetylase (HDAC) bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. Among them, the most potent compound, 2o, inhibited c-Met kinase and HDACs, with IC50 values of 9.0 and 31.6 nM, respectively, and showed efficient antiproliferative activities against both A549 and HCT-116 cancer cell lines with greater potency than an equimolar mixture of the respective inhibitors of the two enzymes: crizotinib and vorinostat (SAHA). Our study provided an efficient strategy for the discovery of multitargeted antitumor drugs.

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Design, synthesis and biological evaluation of novel histone deacetylase inhibitors incorporating 4-aminoquinazolinyl systems as capping groups

Cited by 15 publications

References 19 publications

Quinazoline‐Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Quinazoline‐Based Hydroxamic Acids: Design, Synthesis, and Evaluation of Histone Deacetylase Inhibitory Effects and Cytotoxicity

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

Design, Synthesis, and Biological Evaluation of Dual c-Met/HDAC Inhibitors Bearing 2-Aminopyrimidine Scaffold

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