Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif

Yang, Jinyu; Cheng, Gaoliang; Xu, Qihao; Luan, Shenglin; Wang, Shuxiang; Liú, Dan; Zhao, Liang

doi:10.1016/j.bmc.2017.08.029

Cited by 18 publications

(8 citation statements)

References 23 publications

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“…The different HDAC6 inhibitory activity between compounds 4 and 6 resulted from the different length of their linkers. It has been demonstrated that the length of the linker connecting the N-hydroxybenzamide group and the terminal cap group is crucial for HDAC6 inhibition. ,,,, In our case, the linker containing two sp 3 atoms (one carbon and one oxygen in compound 4 ) was preferable to the linker containing only one sp 3 atom (the oxygen in compound 6 ). This trend was also observed in other reported HDAC6 inhibitors. ,, It is worth noting that there were also structure–activity relationship studies showing that the linker containing only one sp 3 atom was more favorable for HDAC6 inhibition. , This discrepancy could be ascribed to the different steric hindrance, hydrophobicity, and hydrogen-bonding ability of different cap groups in HDAC6 inhibitors.…”

Section: Resultsmentioning

confidence: 65%

“…18,29,30 It is worth noting that there were also structure−activity relationship studies showing that the linker containing only one sp 3 atom was more favorable for HDAC6 inhibition. 32,33 This discrepancy could be ascribed to the different steric hindrance, 1 were also evaluated. All compounds were tested at the concentration of 2 μM.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

Liu

Chai

et al. 2023

J. Med. Chem.

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In our previous research, a series of phenylsulfonylfuroxan-based hydroxamates were developed, among which compound 1 exhibited remarkable in vitro and in vivo antitumor potency due to its histone deacetylase (HDAC) inhibitory and nitric oxide (NO)-donating activities. Herein, the in-depth study of compound 1 revealed that this HDAC inhibitor-NO donor hybrid could enduringly increase the intracellular levels of acetyl histones and acetyl α-tubulin, which could be ascribed to its irreversible inhibition toward class I HDACs and HDAC6. Structural modification of compound 1 led to a novel phenylsulfonylfuroxan-based hydroxamate 4, which exhibited considerable HDAC6 inhibitory activity and selectivity. Furthermore, compound 4 could inhibit intracellular HDAC6 both selectively and irreversibly. To the best of our knowledge, this is the first research reporting the irreversible inhibition of HDAC6. It was also demonstrated that compared with ACY-241 (a reversible HDAC6 inhibitor in clinical trials), the irreversible HDAC6 selective inhibitor 4 exhibited not only superior anti-multiple myeloma activity but also improved therapeutic index.

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Section: Resultsmentioning

confidence: 65%

Section: ■ Results and Discussionmentioning

confidence: 99%

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

Liu

Chai

et al. 2023

J. Med. Chem.

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“…Moreover, the 1,3-benzodioxole moiety has been explored for the optimization of structurally diverse classes of HDAC6 inhibitors, with promising results. [21][22][23] The three chemical moieties emerging from these analyses were assembled into compound 11a, a substituted aminotriazoloquinazoline derivative. The connectivity between the three fragments was inspired by information available from HDAC6 crystal structures in complex with ligands and then veried by means of extensive similarity estimations (see ESI †) and docking (see below).…”

Section: Design Of Aminotriazoloquinazoline Compounds Based On Chemoi...mentioning

confidence: 99%

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

et al. 2022

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“…Pyrazoline ring has been identified as an appropriate surface recognition motif in designing of HDAC inhibitors, [49][50][51] to ascertain HDAC inhibitory potential, we undertook preliminary HDAC screening of S1-S13 on two isoforms of HDACs, HDAC 4 (Class II HDAC) and HDAC 8 (Class I HDAC) belonging to two different HDAC classes. A single dose of 50 μM of each test compound was used in preliminary screening, and residual percentage HDAC activity observed is presented in Figure 6 and details are presented in Supporting Information Tables ST1 and ST2.…”

Section: Hdac Activity Assaymentioning

confidence: 99%

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents

et al. 2020

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In search of novel and effective antitumor agents, pyrazolinesubstituted pyrrolidine-2,5-dione hybrids were designed, synthesized and evaluated in silico, in vitro and in vivo for anticancer efficacy. All the compounds exhibited remarkable cytotoxic effects in MCF7 and HT29 cells. The excellent antiproliferative activity toward MCF7 (IC 50 = 0.78 � 0.01 μM), HT29 (IC 50 = 0.92 � 0.15 μM) and K562 (IC 50 = 47.25 � 1.24 μM) cell lines, prompted us to further investigate the antitumor effects of the best compound S2 (1-(2-(3-(4-fluorophenyl)-5-(ptolyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-oxoethyl)pyrrolidine-2,5-dione). In cell-cycle analysis, S2 was found to disrupt the growth phases with increased cell population in G 1 /G 0 phase and decreased cell population in G 2 /M phase. The excellent in vitro effects were also supported by inhibition of anti-apoptotic protein Bcl-2. In vivo tumor regression studies of S2 in HT29 xenograft nude mice, exhibited equivalent and promising tumor regression with maximum TGI, 66 % (i. p. route) and 60 % (oral route) at 50 mg kg À 1 dose by both the routes, indicating oral bioavailability and antitumor efficacy. These findings advocate that hybridization of pyrazoline and pyrrolidine-2,5dioes holds promise for the development of more potent and less toxic anticancer agents.

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Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif

Cited by 18 publications

References 23 publications

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

Discovery of the First Irreversible HDAC6 Isoform Selective Inhibitor with Potent Anti-Multiple Myeloma Activity

Synthesis of potent and selective HDAC6 inhibitors led to unexpected opening of a quinazoline ring

Synthesis and Biological Evaluation of Pyrazoline and Pyrrolidine‐2,5‐dione Hybrids as Potential Antitumor Agents

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