Synthesis, Biological Evaluation and Molecular Modeling of Substituted Indeno[1,2-b]indoles as Inhibitors of Human Protein Kinase CK2

Alchab, Faten; Ettouati, Laurent; Bouaziz, Zouhair; Bollacke, Andre; Delcros, Jean‐Guy; Gertzen, Christoph G. W.; Gohlke, Holger; Pinaud, Noël; Marchivie, Mathieu; Guillon, Jean; Fenêt, Bernard; Jose, Joachim; Borgne, Marc Le

doi:10.3390/ph8020279

Cited by 34 publications

(28 citation statements)

References 29 publications

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“…Table 1. Structures of the ketonic indeno [1,2-b]indoles and their IC50 values towards CK2, which were used for the training and test sets, data from Alchab et al [9] and Gozzi et al [13]. MOE software (Chemical Computing Group, Montreal, Canada) package was used to perform this study [21].…”

Section: Resultsmentioning

confidence: 99%

<strong>Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining</strong>

Haidar

Bouaziz

Marminon

et al. 2017

Proceedings of 3rd International Electronic Conference on Medicinal Chemistry

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Abstract:Casein kinase 2 is a ubiquitous kinase protein emerging as a target for the treatment of cancer. Several active CK2 inhibitors have been developed in the last few years; most of them have ATP-competitive type of inhibition. Indeno [1,2-b]indoles present a class of natural and synthetic compounds; many of them have different bioactivity. Here we report on the development of a ligand-based pharmacophore on the basis of different active Indeno[1,2-b]indoles (training set), the pharmacophore model was challenged against small library of Indeno[1,2-b]indoles (test set), the study was performed using MOE software. Our model demonstrates good performance in the test set, 85% of the medium or high inhibitory activity compounds were identified, while only 17% of the low or no inhibitory activity compounds were misclassified. Several structures were suggested as possible active CK2 inhibitors by using this model as a base for search in the ZINC database among them was bikaverin which was then further studied.

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Section: Resultsmentioning

confidence: 99%

<strong>Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining</strong>

Haidar

Bouaziz

Marminon

et al. 2017

Proceedings of 3rd International Electronic Conference on Medicinal Chemistry

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“…Key enaminones 1 h,i were synthetized as previously described 20,28 . The synthesis of indeno[1,2-b]indoloquinones 5a-g (see also Table 1 Screening by MALDI mass spectrometry MALDI Mass spectrometry is used to determine whether a molecule has a chance to be a good candidate for the inhibition of CDC25s.…”

Section: Synthesis Of the Targeted Indeno[12-b]indoloquinonesmentioning

confidence: 99%

Screening of indeno[1,2-b]indoloquinones by MALDI-MS: a new set of potential CDC25 phosphatase inhibitors brought to light

Alchab

Sibille

Ettouati

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Up to now, the most common strategy to inhibit CK2 was to design small molecules that target the ATP-binding catalytic site [11]. A large number of compounds with different scaffolds have been described as active CK2 inhibitors [11][12][13][14], including compounds with an indeno [1,2-b]indole scaffold [15][16][17][18][19][20]. Among all known CK2 inhibitors, only one compound, 5-(3-chloro-phenylamino)-benzo[c] [2,6]naphthyridine-8-carboxylic acid (CX-4945, Silmitasertib), has entered into clinical trial (phase II) as an orally available and selective inhibitor of protein kinase CK2 for the treatment of different kinds of cancer [21,22].…”

Section: Introductionmentioning

confidence: 99%

QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

et al. 2019

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Casein kinase II (CK2) is an intensively studied enzyme, involved in different diseases, cancer in particular. Different scaffolds were used to develop inhibitors of this enzyme. Here, we report on the synthesis and biological evaluation of twenty phenolic, ketonic, and para-quinonic indeno[1,2-b]indole derivatives as CK2 inhibitors. The most active compounds were 5-isopropyl-1-methyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4h and 1,3-dibromo-5-isopropyl-5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione 4w with identical IC50 values of 0.11 µM. Furthermore, the development of a QSAR model based on the structure of indeno[1,2-b]indoles was performed. This model was used to predict the activity of 25 compounds with naphtho[2,3-b]furan-4,9-dione derivatives, which were previously predicted as CK2 inhibitors via a molecular modeling approach. The activities of four naphtho[2,3-b]furan-4,9-dione derivatives were determined in vitro and one of them (N-isopentyl-2-methyl-4,9-dioxo-4,9-dihydronaphtho[2,3-b]furan-3-carboxamide) turned out to inhibit CK2 with an IC50 value of 2.33 µM. All four candidates were able to reduce the cell viability by more than 60% after 24 h of incubation using 10 µM.

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Synthesis, Biological Evaluation and Molecular Modeling of Substituted Indeno[1,2-b]indoles as Inhibitors of Human Protein Kinase CK2

Cited by 34 publications

References 29 publications

<strong>Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining</strong>

<strong>Development of Pharmacophore Model for Indeno[1,2-b]indoles as Human Protein Kinase CK2 Inhibitors and Database Mining</strong>

Screening of indeno[1,2-b]indoloquinones by MALDI-MS: a new set of potential CDC25 phosphatase inhibitors brought to light

QSAR Model of Indeno[1,2-b]indole Derivatives and Identification of N-isopentyl-2-methyl-4,9-dioxo-4,9-Dihydronaphtho[2,3-b]furan-3-carboxamide as a Potent CK2 Inhibitor

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