Appraisal of GABA and PABA as linker: Design and synthesis of novel benzamide based histone deacetylase inhibitors

Rajak, Harish; Kumar, Pramod; Parmar, Poonam; Thakur, Bhupendra Singh; Veerasamy, Ravichandran; Sharma, Prabodh Chander; Sharma, Ajay; Gupta, Arun Kumar; Dangi, J. S.

doi:10.1016/j.ejmech.2012.03.058

Cited by 22 publications

(13 citation statements)

References 21 publications

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“…Its modified compounds also appeared to have a good inhibitory activity against HDACs both in vitro and in vivo evaluation (Rajak et al, 2012). Then as a hydrophobic cap (CAP), acetamide group was chosen as connecting unit (CU) and a hydrophobic group -R that may interact with the HDAC cavity surface (Rajak et al, 2012). The general structure of the class II HDAC inhibitor in this study is seen in Fig.…”

Section: Hdac Inhibitor (Hdaci) Ligands Designmentioning

confidence: 98%

“…As a linker, paraaminobenzoic acid (PABA) was chosen as it has been shown to have strong interaction with hydrophobic residues on HDAC cylindrical pocket. Its modified compounds also appeared to have a good inhibitory activity against HDACs both in vitro and in vivo evaluation (Rajak et al, 2012). Then as a hydrophobic cap (CAP), acetamide group was chosen as connecting unit (CU) and a hydrophobic group -R that may interact with the HDAC cavity surface (Rajak et al, 2012).…”

Section: Hdac Inhibitor (Hdaci) Ligands Designmentioning

confidence: 99%

“…HDACs play an important role in the process of deacetylation or acetyl group release within histone protein tails, that cause histones to be tightly twisted with DNA, thereby inhibiting transcription of tumor suppressor genes and causing tumors to grow into cancer cells Tambunan et al, 2011). Thus, HDAC inhibition has become a potential and effective strategy for inducing growth arrest, differentiation and apoptosis of cancer cells in cervical cancer therapy (Rajak et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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In silico identification of 2-oxo-1,3-thiazolidine derivatives as novel inhibitor candidate of class II histone deacetylase (HDAC) in cervical cancer treatment

Tambunan

Parikesit

Ghifari

et al. 2019

Arabian Journal of Chemistry

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Cervical cancer ranks third among the most prevalent deadly cancer in women worldwide and ranks first in developing countries. It is caused by human papilloma virus (HPV) infection. Thus HDACs have become prominent inhibition target for cervical cancer treatment. In order to discover the new alternative HDAC inhibitors (HDACIs), we conducted a computer-aided drug discovery and development (CADDD) based on de novo approach. The compound library is based on 4-[(2-oxo-1,3-thiazolidin-3-yl)carbonyl] aniline. Screening of the best drug leads was evaluated from several parameters, such as docking and interaction analysis, pharmacology, in silico preclinical trial and molecular dynamics analysis. The inhibitory activity of these new designed ligands against Homo sapiens class II HDAC was determined by molecular docking simulation. Docking analysis yielded eight best ligands which have better binding affinity than the standards. Therefore, interaction analysis indicated that all best ligands performed coordination with Zn 2+ cofactor in HDAC charge-relay system which are essential for HDAC inhibitory activities of these inhibitors. Pharmacology analysis and preclinical trials of these compounds including pharmacology properties, bioactivity, mutagenicity-carcinogenicity, absorption, distribution, metabolism, excretion and toxicity (ADMET) properties were done through in silico methods. Through this analysis, the best ligands meet Lipinski's rule of five, have a better drug score than standards, and show good bioactivities, oral bioavailability and ADMET properties. All best ligands also have good synthetic accessibility and were proved to be new compounds that have never been synthesized

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Section: Hdac Inhibitor (Hdaci) Ligands Designmentioning

confidence: 98%

Section: Hdac Inhibitor (Hdaci) Ligands Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In silico identification of 2-oxo-1,3-thiazolidine derivatives as novel inhibitor candidate of class II histone deacetylase (HDAC) in cervical cancer treatment

Tambunan

Parikesit

Ghifari

et al. 2019

Arabian Journal of Chemistry

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“…It is the liaison between CAP and ZBG that forms a short-chain hydrocarbons, long-chain hydrocarbons or aromatic such as butane, fatty acids, γ -aminobutyric acid (GABA), p-aminobenzoic acid (PABA), furans, and others [35]. The linker is able to interact with amino acid residues found in the cylinder pocket of HDAC enzymes [36]. …”

Section: Introductionmentioning

confidence: 99%

Utilization of Boron Compounds for the Modification of Suberoyl Anilide Hydroxamic Acid as Inhibitor of Histone Deacetylase Class II Homo sapiens

Bakri

Parikesit

Satriyanto

et al. 2014

Advances in Bioinformatics

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Histone deacetylase (HDAC) has a critical function in regulating gene expression. The inhibition of HDAC has developed as an interesting anticancer research area that targets biological processes such as cell cycle, apoptosis, and cell differentiation. In this study, an HDAC inhibitor that is available commercially, suberoyl anilide hydroxamic acid (SAHA), has been modified to improve its efficacy and reduce the side effects of the compound. Hydrophobic cap and zinc-binding group of these compounds were substituted with boron-based compounds, whereas the linker region was substituted with p-aminobenzoic acid. The molecular docking analysis resulted in 8 ligands with ΔG binding value more negative than the standards, SAHA and trichostatin A (TSA). That ligands were analyzed based on the nature of QSAR, pharmacological properties, and ADME-Tox. It is conducted to obtain a potent inhibitor of HDAC class II Homo sapiens. The screening process result gave one best ligand, Nova2 (513246-99-6), which was then further studied by molecular dynamics simulations.

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“…The starting compounds, ethyl 2-amino-4,5,6,7-tetrahydro [1]benzothiophene-3-carboxylate (1), 32 3-benzyl-2-sulphanyl-5,6,7,8-tetrahydro [1]benzothieno [2,3- (2) 33 and the α-and β-chloroamides (13a-d, 14a-d, 15a-d) [34][35][36][37][38][39][40] were prepared according to reported procedures. A mixture of 3 (0.32 g, 1 mmol) and acetic acid (10 mL, 70 mmol) was heated under reflux for 6 h. The reaction mixture was poured onto ice cold water (25 mL).…”

Section: Chemistrymentioning

confidence: 99%

Synthesis, Characterization and Cytotoxicity of substituted[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidines

Botros¹,

Khalil²,

Kamel³

et al. 2017

ACSi

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A new series of 4-benzyl-6,7,8,9-tetrahydro[1]benzothieno [3,2-e] [1,2,4]triazolo [4,3-a]pyrimidines was synthesized motivated by the widely reported anticancer activity of thieno [2,3-d]pyrimidines and triazolothienopyrimidines. The in vitro cytotoxic activity of some selected compounds was evaluated against two human cell lines: prostate cancer (PC-3) and colon cancer (HCT-116). A preliminary study of the structure-activity relationship of the target compounds was discussed. Most of the synthesized compounds showed remarkable activity on the tested cell lines, while compound 16c had the highest potency against the PC-3 cell line with an IC 50 of 5.48 μM compared to Doxorubicin (IC 50 = 7.7 μM), the reference standard used in this study. On the other hand, 6c and 18c were the most active against HCT-116 (IC 50 = 6.12 and 6.56 μM, respectively) relative to IC 50 = 15.82 μM of the standard. Thus, some of the synthesized thienopyrimidine derivatives, specially 6c, 16c and 18c, have the potential to be developed into potent anticancer agents.

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Appraisal of GABA and PABA as linker: Design and synthesis of novel benzamide based histone deacetylase inhibitors

Cited by 22 publications

References 21 publications

In silico identification of 2-oxo-1,3-thiazolidine derivatives as novel inhibitor candidate of class II histone deacetylase (HDAC) in cervical cancer treatment

In silico identification of 2-oxo-1,3-thiazolidine derivatives as novel inhibitor candidate of class II histone deacetylase (HDAC) in cervical cancer treatment

Utilization of Boron Compounds for the Modification of Suberoyl Anilide Hydroxamic Acid as Inhibitor of Histone Deacetylase Class II Homo sapiens

Synthesis, Characterization and Cytotoxicity of substituted[1]benzothieno[3,2-e][1,2,4]triazolo[4,3-a]pyrimidines

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