4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors

Fréchette, Sylvie; Leit, Silvana; Woo, Soon Hyung; Lapointe, Guillaume; Jeannotte, Guillaume; Moradei, Oscar; Paquin, Isabelle; Bouchain, Giliane; Raeppel, Stéphane; Gaudette, Frédéric; Zhou, Nancy; Vaisburg, A. F.; Fournel, Marielle; Yan, Pu; Trachy-Bourget, Marie-Claude; Kalita, Ann; Robert, Mathieu; Lu, Aihua; Rahil, Jubrail; MacLeod, A. Robert; Besterman, Jeffrey M.; Li, Zuomei; Delorme, Daniel

doi:10.1016/j.bmcl.2007.12.057

Cited by 14 publications

(16 citation statements)

References 23 publications

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“…A set of 48 aminophenyl benzamide derivatives with well defined HDAC1 inhibitory activity (given as IC 50 values in μM concentration) taken from Moradei and Fr chette et al [16,17] was used for the present analysis. For the correlation purpose, the IC 50 values were converted to their molar values and subsequently to their free energy related terms i.e., log(1/IC 50 ) or -log(IC 50 ).…”

Section: Methodsmentioning

confidence: 99%

“…Thus, there has been considerable interest in developing non-hydroxamate HDAC inhibitors. 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides represent an important class of non-hydroxamate HDACIs owing to their potent HDAC inhibition and excellent selectivity for HDAC class I enzyme [16,17].…”

Section: Introductionmentioning

confidence: 99%

“…With a view of progression of this class of inhibitors and our continuing interest in the development of HDACIs [18,19], a quantitative structure activity relationship analysis was proposed on the series of aminophenyl benzamide derivatives reported for HDAC1 inhibitory activity by Moradei and Fr chette et al [16,17]. The compounds reported in two articles were combined to a single dataset for the purpose of QSAR modeling since the compounds reported have a common scaffold and the work has been carried out in the same lab.…”

Section: Introductionmentioning

confidence: 99%

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3D QSAR of Aminophenyl Benzamide Derivatives as Histone Deacetylase Inhibitors

Mahipal

Tanwar²,

Karthikeyan³

et al. 2010

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The article describes the development of a robust pharmacophore model and the investigation of structure activity relationship analysis of 48 aminophenyl benzamide derivatives reported for Histone Deacetylase (HDAC) inhibition using PHASE module of Schrodinger software. A five point pharmacophore model consisting of two aromatic rings (R), two hydrogen bond donors (D) and one hydrogen bond acceptor (A) with discrete geometries as pharmacophoric features was developed and the generated pharmacophore model was used to derive a predictive atom-based 3D QSAR model for the studied dataset. The obtained 3D QSAR model has an excellent correlation coefficient value (r(2)=0.99) along with good statistical significance as shown by high Fisher ratio (F=631.80). The model also exhibits good predictive power confirmed by the high value of cross validated correlation coefficient (q(2) = 0.85). The QSAR model suggests that hydrophobic character is crucial for the HDAC inhibitory activity exhibited by these compounds and inclusion of hydrophobic substituents will enhance the HDAC inhibition. In addition to the hydrophobic character, hydrogen bond donating groups positively contributes to the HDAC inhibition whereas electron withdrawing groups has a negative influence in HDAC inhibitory potency. The findings of the QSAR study provide a set of guidelines for designing compounds with better HDAC inhibitory potency.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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3D QSAR of Aminophenyl Benzamide Derivatives as Histone Deacetylase Inhibitors

Mahipal

Tanwar²,

Karthikeyan³

et al. 2010

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“…(4), compound 39) inhibited tumor growth in mice bearing HCT 116 xenografts by 88% compared to a control and 89.6% in mice carrying SW-48 xenografts. Additional data of similar compounds from MethylGene can also be found in the literature [71][72][73].…”

Section: Aminobenzanilidesmentioning

confidence: 95%

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Moradei¹,

Vaisburg²,

Martell³

2008

CTMC

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Histone deacetylase (HDAC) inhibitors constitute a novel and growing class of anticancer agents that function by altering intracellular patterns of histone acetylation, the so-called epigenetic "histone code," thereby producing changes in cell cycle arrest, differentiation, and/or apoptosis in tumor cells. This overview describes the chemistry and preliminary characterization of recently disclosed molecules in three major classes of HDAC inhibitors: hydroxamic acids, 2-amino- benzanilides, and cyclic peptides. In addition, results from recent clinical trials on isotype-selective HDAC inhibitors are reviewed. It is clear from the plethora of new molecules and the encouraging results from clinical trials that HDAC inhibitors hold a great deal of promise, particularly as add-on therapy, for the treatment of a variety of solid and hematologic cancers.

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“…administration (59% TGI at 40 mg/kg), 42b also shows efficacy following oral administration at 80 mg/kg, with 55 and 67% TGI in NSCLC A549 and prostate DU145 xenografts. Other potent analogs have been developed by the scientists in Montreal with a series of 4-(heteroarylaminomethyl) derivatives [58]. Starting from modestly active imidazole sulfide 43a (IC 50 ¼ 0.5 mM), this group was able to improve the enzymatic activity more than 15-fold to give a 2-aminobenzothiazole analog 43b (IC 50 ¼ 30 nM).…”

Section: Histone Deacetylase Inhibitors J201mentioning

confidence: 99%

Histone Deacetylase Inhibitors

Jones

2009

Methods and Principles in Medicinal Chemistry

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4-(Heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides and their analogs as a novel class of histone deacetylase inhibitors

Cited by 14 publications

References 23 publications

3D QSAR of Aminophenyl Benzamide Derivatives as Histone Deacetylase Inhibitors

3D QSAR of Aminophenyl Benzamide Derivatives as Histone Deacetylase Inhibitors

Histone Deacetylase Inhibitors in Cancer Therapy: New Compounds and Clinical Update of Benzamide-Type Agents

Histone Deacetylase Inhibitors

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