N3-Arylmalonamides: A new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases

Saavedra, Oscar M.; Claridge, Stephen; Zhan, Lijie; Raeppel, Franck; Granger, Marie-Claude; Raeppel, Stéphane; Mannion, Michael R.; Gaudette, Frédéric; Zhou, Nancy; Isakovic, Ljubomir; Bernstein, Naomy; Déziel, Robert; Nguyen, Hannah; Beaulieu, Normand; Beaulieu, Carole; Dupont, Isabelle; Wang, Jinru; MacLeod, A. Robert; Besterman, Jeffrey M.; Vaisburg, A. F.

doi:10.1016/j.bmcl.2009.10.095

Cited by 27 publications

(19 citation statements)

References 30 publications

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“…Cells were harvested following a 24 h and/or 48 h and further processed according to the following protocols.For cell cycle profile analysis, following 24 h treatment cells were fixed in 70% ice-cold ethanol and kept at 4ºC for at least 12 h until analysis. Prior to analysis, cells were incubated with Propidium Iodide (5 µg/mL) and RNaseA in PBS (100 µg/ml) for 30 min on ice [11].…”

Section: Analysis Of Cell Cycle Profile and Programmed Cell Deathmentioning

confidence: 99%

“…The thienopyridine skeleton has been reported as having interesting biological activities namely antitumoral [1][2][3][4][5][6][7] and antiangiogenic [8][9][10][11][12]. Sugano et al reported that the (3-amino-6-thien-2-yl-thieno [2,3-b]pyridin-2-yl)arylmethanones I showed selectivity against a tumorigenic cell line, in very low EC 50 values [1].…”

Section: Introductionmentioning

confidence: 99%

“…Effects on the cell cycle profile of the NCI-H460 cells treated with compound VII were observed [7]. N-(1H-indol-5-yl)-2-arylthieno[3,2-b]pyridin-7-amines [8], aminothieno [3,2-c]pyridine 1,3-diarylureas [9], thieno [3,2-b]pyridine arylethers phenylacetylthioureas [10], thieno [3,2-b]pyridine arylethers N 3 -arylmalonamides [11], and N- (3-fluoro-4-(2-5 arylthieno [3,2-b]pyridin-7-yloxy)phenyl)-2-oxo-3-phenylimidazolidine-1-carboxamides [12] have been previously described as inhibitors of the vascular endothelial growth factor receptor (VEGFR-2), a mediator of the biological function of the vascular endothelial growth factor (VEGF), related to angiogenesis and metastasis.…”

Section: Introductionmentioning

confidence: 99%

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New di(hetero)arylethers and di(hetero)arylamines in the thieno[3,2-b]pyridine series: Synthesis, growth inhibitory activity on human tumor cell lines and non-tumor cells, effects on cell cycle and on programmed cell death

Queiroz

Peixoto

Calhelha

et al. 2013

European Journal of Medicinal Chemistry

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Section: Analysis Of Cell Cycle Profile and Programmed Cell Deathmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New di(hetero)arylethers and di(hetero)arylamines in the thieno[3,2-b]pyridine series: Synthesis, growth inhibitory activity on human tumor cell lines and non-tumor cells, effects on cell cycle and on programmed cell death

Queiroz

Peixoto

Calhelha

et al. 2013

European Journal of Medicinal Chemistry

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“…[12][13][14][15] Magnetoliposomes are specially promising as nanocarriers for potential antitumor drugs. Thienopyridine derivatives have been reported as possessing antiangiogenic, [16][17][18][19][20][21] antitumor, [21][22][23][24][25][26][27][28][29] or both activities. 30 Among the potential antitumor di(hetero)arylamines in the thieno [3,2-b]pyridine series, prepared earlier by some of us, the ones with an o-methoxy or m-methoxy groups relative to the NH (compounds 1 and 2, Fig.…”

Section: Introductionmentioning

confidence: 99%

Magnetoliposomes as carriers for promising antitumor thieno[3,2-b]pyridin-7-arylamines: photophysical and biological studies

et al. 2017

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Magnetoliposomes containing superparamagnetic manganese ferrite nanoparticles were tested as nanocarriers for two new promising antitumor drugs, a N-(3-methoxyphenyl)thieno[3,2-b]pyridin-7-amine (1) and a N-(2-methoxy-phenyl)thieno[3,2-b]pyridin-7-amine (2). The fluorescence emission of both compounds was studied in different polar and non-polar media, evidencing a strong intramolecular charge transfer character of the excited state of both compounds. These in vitro potent antitumor thienopyridine derivatives were successfully incorporated in both aqueous and solid magnetoliposomes, with encapsulation efficiencies higher than 75%. The magnetic properties of magnetoliposomes containing manganese ferrite nanoparticles were measured for the first time, proving a superparamagnetic behaviour. Growth inhibition assays on several human tumor cell lines showed very low GI 50 values for drug-loaded aqueous magnetoliposomes, comparing in most cell lines with the ones previously obtained using the neat compounds. These results are important for future drug delivery applications using magnetoliposomes in oncology, through a dual therapeutic approach (simultaneous chemotherapy and magnetic hyperthermia).

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“…And the structureactivity relationships of the c-Met type II inhibitors to c-Met were systematically investigated based on the computationally determined binding modes. The large number of c-Met inhibitors with reported activities [9,[15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] as well as the six c-Met crystal structures (pdb code: 2WGJ, 2WKM, 3ZXZ, 3ZZE, 3LQ8 and 3U6I) [11,12,14,32] in complex with some of these inhibitors gave rise to the possibility to test our methods.…”

Section: Introductionmentioning

confidence: 99%

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

Kaas

et al. 2017

Journal of Molecular Graphics and Modelling

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Graphical AbstractTOC c-Met is a tyrosine kinase and an important therapeutic target for anticancer drugs. In present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding energies of type II c-Met inhibitors. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design. Highlights• Testing a set of influences to the ranking ability of the docking program in MOE.• Structure-activity relationship study of c-Met type II inhibitors.• Establishing an efficient computational docking approach for c-Met type II inhibitors design.ABSTRACT： c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation sampling strategies, and conformations of the binding site captured in several crystallographic structures. Our results suggest that the force fields, the protein flexibility, and the selected conformation of the binding site substantially influence the correlation coefficient, while the sampling strategies and ensemble docking only mildly affect the prediction accuracy. Structure-activity relationship study suggests that the structural determinants to the high binding affinity of the type II inhibitors originate from its overall linear shape, hydrophobicity, and two conserved hydrogen bonds. Results from this study will form the basis for establishing an efficient computational docking approach for c-Met type II inhibitors design.

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N3-Arylmalonamides: A new series of thieno[3,2-b]pyridine based inhibitors of c-Met and VEGFR2 tyrosine kinases

Cited by 27 publications

References 30 publications

New di(hetero)arylethers and di(hetero)arylamines in the thieno[3,2-b]pyridine series: Synthesis, growth inhibitory activity on human tumor cell lines and non-tumor cells, effects on cell cycle and on programmed cell death

New di(hetero)arylethers and di(hetero)arylamines in the thieno[3,2-b]pyridine series: Synthesis, growth inhibitory activity on human tumor cell lines and non-tumor cells, effects on cell cycle and on programmed cell death

Magnetoliposomes as carriers for promising antitumor thieno[3,2-b]pyridin-7-arylamines: photophysical and biological studies

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors

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