N2-Trimethylacetyl substituted and unsubstituted-N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrim idine-2,4-diamines: design, cellular receptor tyrosine kinase inhibitory activities and in vivo evaluation as antiangiogenic, antimetastatic and antitumor agents.
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Gangjee A, Namjoshi OA, Yu J, Ihnat MA, Thorpe JE, Bailey-Downs LC
N2-Trimethylacetyl substituted and unsubstituted-N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrim idine-2,4-diamines: design, cellular receptor tyrosine kinase inhibitory activities and in vivo evaluation as antiangiogenic, antimetastatic and antitumor agents.
Bioorg Med Chem. 2013 Mar 1;21(5):1312-23. doi: 10.1016/j.bmc.2012.12.045. Epub 2013 Jan 10.
- PubMed ID
- 23375090 [ View in PubMed]
- Abstract
Six novel N(4)-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-di amines and their N(2)-trimethylacetyl substituted analogs were synthesized as receptor tyrosine kinase (RTK) inhibitors. A microwave-mediated Sonogashira reaction was used as a key step for the synthesis of these compounds. Biological evaluation, in whole cell assays, showed that some analogs had remarkable inhibitory activity against a variety of RTKs and in particular cytotoxic activity against A431 tumor cells in culture. The inhibitory data against RTKs in this study demonstrated that variation of the 4-anilino substituents of these analogs dictates both potency and specificity of inhibitory activity against various RTKs. The study also supported the hypothesis that interaction of substituents on the 2-amino group with hydrophobic site-II provides an increase in potency. Compound 8 of this series was selected for evaluation in vivo in a B16-F10 syngeneic mouse tumor model and exhibited significant reduction in tumor growth rate, in tumor vascular density and in metastases to the lung compared to the control.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Erlotinib Epidermal growth factor receptor IC 50 (nM) 1200 N/A N/A Details Semaxanib Vascular endothelial growth factor receptor 2 IC 50 (nM) 12000 N/A N/A Details Sunitinib Platelet-derived growth factor receptor beta IC 50 (nM) 83100 N/A N/A Details Sunitinib Vascular endothelial growth factor receptor 2 IC 50 (nM) 18900 N/A N/A Details