Novel 4-Oxoquinazoline-Based<i>N</i>-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

Anh, Duong Tien; Pham-The, Hai; Huy, Le D; Ngoc, Hoang B; Ngoc, Trinh T M; Dung, Do Thi Mai; Park, Eun Jeong; Song, In K; Kang, Jong Soon; Kwon, Joo-Hee; Tung, Truong Thanh; Han, Sang‐Bae; Nam, Nguyen Hai

doi:10.1021/acsomega.0c05870

Cited by 11 publications

(4 citation statements)

References 41 publications

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“…Most of these compounds displayed good to potent HDAC inhibitory efficacy and cytotoxicity (SW620—colon cancer, PC-3—prostate cancer, and NCI-H23—lung cancer). With an IC 50 value of 12 nM, compound F was the most potent HDAC6 inhibitor [ 45 ]. Doan Thanh Hieu and colleagues developed novel small compounds for HDAC inhibition.…”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-one-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity

Khetmalis

Ashna

Schweipert

et al. 2023

IJMS

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A series of novel quinazoline-4-(3H)-one derivatives were designed and synthesized as histone deacetylase 6 (HDAC6) inhibitors based on novel quinazoline-4-(3H)-one as the cap group and benzhydroxamic acid as the linker and metal-binding group. A total of 19 novel quinazoline-4-(3H)-one analogues (5a–5s) were obtained. The structures of the target compounds were characterized using 1H-NMR, 13C-NMR, LC–MS, and elemental analyses. Characterized compounds were screened for inhibition against HDAC8 class I, HDAC4 class IIa, and HDAC6 class IIb. Among the compounds tested, 5b proved to be the most potent and selective inhibitor of HDAC6 with an IC50 value 150 nM. Some of these compounds showed potent antiproliferative activity in several tumor cell lines (HCT116, MCF7, and B16). Amongst all the compounds tested for their anticancer effect against cancer cell lines, 5c emerged to be most active against the MCF-7 line with an IC50 of 13.7 μM; it exhibited cell-cycle arrest in the G2 phase, as well as promoted apoptosis. Additionally, we noted a significant reduction in the colony-forming capability of cancer cells in the presence of 5c. At the intracellular level, selective inhibition of HDAC6 was enumerated by monitoring the acetylation of a-tubulin with a limited effect on acetyl-H3. Importantly, the obtained results suggested a potent effect of 5c at sub-micromolar concentrations as compared to the other molecules as HDAC6 inhibitors in vitro.

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Section: Resultsmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-one-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity

Khetmalis

Ashna

Schweipert

et al. 2023

IJMS

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“…Noticeably, the cytotoxic potency of this compound was 15-times higher than that of vorinostat. More recently, another library of compounds was designed and synthesized by this group keeping the quinazolin-4(3H)-one moiety intact but generating various derivatives by changing substituents at the N-3 position of this aromatic moiety as well as by varying the zinc binder groups (Anh et al, 2021). Similar to earlier investigations, these compounds were tested against multiple cancer cell lines and one of these was PC-3.…”

Section: Development Hdaci Against Prostate Carcinomamentioning

confidence: 95%

Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer

Pramanik

Halder²,

Mukherjee³

et al. 2022

Front. Chem.

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Histone deacetylases (HDACs) are enzymes that play a role in chromatin remodeling and epigenetics. They belong to a specific category of enzymes that eliminate the acetyl part of the histones’ -N-acetyl lysine, causing the histones to be wrapped compactly around DNA. Numerous biological processes rely on HDACs, including cell proliferation and differentiation, angiogenesis, metastasis, gene regulation, and transcription. Epigenetic changes, specifically increased expression and activity of HDACs, are commonly detected in cancer. As a result, HDACi could be used to develop anticancer drugs. Although preclinical outcomes with HDACs as monotherapy have been promising clinical trials have had mixed results and limited success. In both preclinical and clinical trials, however, combination therapy with different anticancer medicines has proved to have synergistic effects. Furthermore, these combinations improved efficacy, decreased tumor resistance to therapy, and decreased toxicity. In the present review, the detailed modes of action, classification of HDACs, and their correlation with different cancers like prostate, breast, and ovarian cancer were discussed. Further, the different cell signaling pathways and the structure-activity relationship and pharmaco-toxicological properties of the HDACi, and their synergistic effects with other anticancer drugs observed in recent preclinical and clinical studies used in combination therapy were discussed for prostate, breast, and ovarian cancer treatment.

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“…Please see Supporting Information for copy of 1 H NMR and 13 C NMR spectra. The configuration of the compound was well established previously [28][29][30][31] .…”

Section: Apoptosis Assaymentioning

confidence: 99%

Design, synthesis and evaluation of novel 2-oxoindoline-based acetohydrazides as antitumor agents

Dung

Park

Anh

et al. 2022

Sci Rep

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In our search for novel small molecules activating procaspase-3, we have designed and synthesized two series of novel (E)-N'-arylidene-2-(2-oxoindolin-1-yl)acetohydrazides (4) and (Z)-2-(5-substituted-2-oxoindolin-1-yl)-N'-(2-oxoindolin-3-ylidene)acetohydrazides (5). Cytotoxic evaluation revealed that the compounds showed notable cytotoxicity toward three human cancer cell lines: colon cancer SW620, prostate cancer PC-3, and lung cancer NCI-H23. Especially, six compounds, including 4f–h and 4n–p, exhibited cytotoxicity equal or superior to positive control PAC-1, the first procaspase-3 activating compound. The most potent compound 4o was three- to five-fold more cytotoxic than PAC-1 in three cancer cell lines tested. Analysis of compounds effects on cell cycle and apoptosis demonstrated that the representative compounds 4f, 4h, 4n, 4o and 4p (especially 4o) accumulated U937 cells in S phase and substantially induced late cellular apoptosis. The results show that compound 4o would serve as a template for further design and development of novel anticancer agents.

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Novel 4-Oxoquinazoline-BasedN-Hydroxypropenamides as Histone Deacetylase Inhibitors: Design, Synthesis, and Biological Evaluation

Cited by 11 publications

References 41 publications

Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-one-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity

Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-one-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity

Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer

Design, synthesis and evaluation of novel 2-oxoindoline-based acetohydrazides as antitumor agents

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