Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1 H -pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study

Wen, Jiachen; Niu, Qun; Liu, Jiang; Bao, Yu; Yang, Jinyu; Luan, Shenglin; Fan, Yinbo; Liú, Dan; Zhao, Liang

doi:10.1016/j.bmcl.2015.12.007

Cited by 22 publications

(12 citation statements)

References 24 publications

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“…The thiol group exposed in this process was supposed to chelate the zinc ion. Many thiol derivatives have been reported by structural modification of SAHA 47 and potent natural products 48 or by de novo design 49–53 . However, none of them has been gained access to the clinical research so far.…”

Section: Classic Zbgsmentioning

confidence: 99%

Zinc binding groups for histone deacetylase inhibitors

Zhang

Jiang

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

187

119

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Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining the potency of HDACIs. Due to the high affinity to the zinc ion, hydroxamic acid is the most commonly used ZBG in the structure of HDACs. An alternative ZBG is benzamide group, which features excellent inhibitory selectivity for class I HDACs. Various ZBGs have been designed and tested to improve the activity and selectivity of HDACIs, and to overcome the pharmacokinetic limitations of current HDACIs. Herein, different kinds of ZBGs are reviewed and their features have been discussed for further design of HDACIs.

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Section: Classic Zbgsmentioning

confidence: 99%

Zinc binding groups for histone deacetylase inhibitors

Zhang

Jiang

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

187

119

View full text Add to dashboard Cite

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“…HDAC (histone deacetylase) inhibitors assay revealed compound 11 ( Figure 7) (IC50 = 0.08 ± 0.01 µM) as highly potent inhibitor against HDACs even three folds of reference drug Vorinostat (IC50 ± SD = 0.25 ± 0.09 µM) and its thiol based analog (IC50 ± SD = 0.26 ± 0.06 µM). Moreover, SAR study revealed that different substituent at N-1 position promoted the inhibition activities of compounds in following decreasing order; -COOH ˃ -OH ˃˃ -R [37]. Esvan Cvijetic et al in 2015 reported the synthesis of pyrazole derivatives containing the carboxylic acid moieties exhibiting excellent inhibition against hCA IX and XII over hCAI and II with suitable inhibition constant values (ki).…”

Section: Anticancer Activitymentioning

confidence: 99%

Pyrazole Bearing Molecules as Bioactive Scaffolds: A Review

Aziz

Zahoor

Ahmad

2020

J. Chil. Chem. Soc.

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Pyrazole being a heterocyclic motif has secured an eccentric status in the field of medicinal chemistry. Pyrazole and its derivatives have tremendous biological applications like anti-cancer, anti-microbial, antiviral, antifungal, anti-inflammatory, analgesic, insecticidal etc. In this review, some recent developments have been reported for the synthesis of biologically active pyrazole based molecules having biological potential such as anti-SIRT1 and SIRT2, anti-FAAH, anti-NOSs, as liver X receptor partial agonist, CB2 receptor ligand and glucagon receptor antagonists.

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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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Novel thiol-based histone deacetylase inhibitors bearing 3-phenyl-1 H -pyrazole-5-carboxamide scaffold as surface recognition motif: Design, synthesis and SAR study

Cited by 22 publications

References 24 publications

Zinc binding groups for histone deacetylase inhibitors

Zinc binding groups for histone deacetylase inhibitors

Pyrazole Bearing Molecules as Bioactive Scaffolds: A Review

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

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