Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy
“…Compound 5b was produced by another method (acid chloride) because the first method was not applicable for this derivative due to the very low yield of final compound ( 5b ). This method conducted by converting the carboxylic acid into acid chloride using oxalyl chloride and DMF in dry dichloromethane which on substitution reaction with different amines in presence of trimethylamine [ 44 – 47 ]. Scheme 1.…”
Background
Liver cancer is predicted to be the sixth most diagnosed cancer globally and fourth leading cause of cancer deaths. In this study, a series of indole-3-isoxazole-5-carboxamide derivatives were designed, synthesized, and evaluated for their anticancer activities. The chemical structures of these of final compounds and intermediates were characterized by using IR, HRMS, 1H-NMR and 13C-NMR spectroscopy and element analysis.
Results
The cytotoxic activity was performed against Huh7, MCF7 and HCT116 cancer cell lines using sulforhodamine B assay. Some compounds showed potent anticancer activities and three of them were chosen for further evaluation on liver cancer cell lines based on SRB assay and real-time cell growth tracking analysis. Compounds were shown to cause arrest in the G0/G1 phase in Huh7 cells and caused a significant decrease in CDK4 levels. A good correlation was obtained between the theoretical predictions of bioavailability using Molinspiration calculation, Lipinski’s rule of five, and experimental verification. These investigations reveal that indole-isoxazole hybrid system have the potential for the development of novel anticancer agents.
Conclusions
This study has provided data that will form the basis of further studies that aim to optimize both the design and synthesis of novel compounds that have higher anticancer activities.
“…Compound 5b was produced by another method (acid chloride) because the first method was not applicable for this derivative due to the very low yield of final compound ( 5b ). This method conducted by converting the carboxylic acid into acid chloride using oxalyl chloride and DMF in dry dichloromethane which on substitution reaction with different amines in presence of trimethylamine [ 44 – 47 ]. Scheme 1.…”
Background
Liver cancer is predicted to be the sixth most diagnosed cancer globally and fourth leading cause of cancer deaths. In this study, a series of indole-3-isoxazole-5-carboxamide derivatives were designed, synthesized, and evaluated for their anticancer activities. The chemical structures of these of final compounds and intermediates were characterized by using IR, HRMS, 1H-NMR and 13C-NMR spectroscopy and element analysis.
Results
The cytotoxic activity was performed against Huh7, MCF7 and HCT116 cancer cell lines using sulforhodamine B assay. Some compounds showed potent anticancer activities and three of them were chosen for further evaluation on liver cancer cell lines based on SRB assay and real-time cell growth tracking analysis. Compounds were shown to cause arrest in the G0/G1 phase in Huh7 cells and caused a significant decrease in CDK4 levels. A good correlation was obtained between the theoretical predictions of bioavailability using Molinspiration calculation, Lipinski’s rule of five, and experimental verification. These investigations reveal that indole-isoxazole hybrid system have the potential for the development of novel anticancer agents.
Conclusions
This study has provided data that will form the basis of further studies that aim to optimize both the design and synthesis of novel compounds that have higher anticancer activities.
“…Compound 286 showed the most potent inhibitory activity against HGC-27 and PC-3 [ 191 ]. A new collection of N -(6-mercaptohexyl)-3-substituted-1 H -pyrazole-5-carboxamide HDAC inhibitors was developed by Wen et al The disulfide compound 287 was found to be potent cytotoxic agent against a panel of seven tumor cells, causing hyperacetylation of histone and non-histone proteins in cellular level, and demonstrated a notable in vivo anti-tumor activity in HCT-116 xeno-grafted model [ 192 ]. Pyrazole-benzimidazole derivatives are novel potent active Chk2 inhibitors were described by Galal et al Out of the synthesized compounds, compound 288 was reported as the most potent effects as Chk2 inhibitors with cytotoxic properties besides their potentiation effects on the cytotoxicity of both cisplatin and doxorubicin, and showed marked antitumor activity as single agent in breast cancer–bearing animals [ 193 ].…”
Pyrazole and its derivatives are considered a pharmacologically important active scaffold that possesses almost all types of pharmacological activities. The presence of this nucleus in pharmacological agents of diverse therapeutic categories such as celecoxib, a potent anti-inflammatory, the antipsychotic CDPPB, the anti-obesity drug rimonabant, difenamizole, an analgesic, betazole, a H2-receptor agonist and the antidepressant agent fezolamide have proved the pharmacological potential of the pyrazole moiety. Owing to this diversity in the biological field, this nucleus has attracted the attention of many researchers to study its skeleton chemically and biologically. This review highlights the different synthesis methods and the pharmacological properties of pyrazole derivatives. Studies on the synthesis and biological activity of pyrazole derivatives developed by many scientists around the globe are reported.
“…Half-life times of the disulfide prodrugs consisting of 70 and 71 moieties were measured in the range of 20.7–49.5 min in human liver microsomes [ 138 ]. In 2016, Wen et al [ 143 ] synthesized pyrazole-containing thiol compounds with class I and IIb preference. The most potent compound 72 had an inhibitory activity in the range of 11–72 nM toward HDAC1–3 and HDAC6 [ 143 ].…”
Section: Thiol Warheadsmentioning
confidence: 99%
“…In 2016, Wen et al [ 143 ] synthesized pyrazole-containing thiol compounds with class I and IIb preference. The most potent compound 72 had an inhibitory activity in the range of 11–72 nM toward HDAC1–3 and HDAC6 [ 143 ]. Regarding in vivo studies, the authors noted that their disulfide compounds were unexpectedly 2–8-fold more potent that their thioester counterparts.…”
Histone deacetylases (HDACs) remove acetyl groups from acetylated lysine residues and have a large variety of substrates and interaction partners. Therefore, it is not surprising that HDACs are involved in many diseases. Most inhibitors of zinc-dependent HDACs (HDACis) including approved drugs contain a hydroxamate as a zinc-binding group (ZBG), which is by far the biggest contributor to affinity, while chemical variation of the residual molecule is exploited to create more or less selectivity against HDAC isozymes or other metalloproteins. Hydroxamates have a propensity for nonspecificity and have recently come under considerable suspicion because of potential mutagenicity. Therefore, there are significant concerns when applying hydroxamate-containing compounds as therapeutics in chronic diseases beyond oncology due to unwanted toxic side effects. In the last years, several alternative ZBGs have been developed, which can replace the critical hydroxamate group in HDACis, while preserving high potency. Moreover, these compounds can be developed into highly selective inhibitors. This review aims at providing an overview of the progress in the field of non-hydroxamic HDACis in the time period from 2015 to present. Formally, ZBGs are clustered according to their binding mode and structural similarity to provide qualitative assessments and predictions based on available structural information.
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