Abstract:
:Six novel N(4)-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines 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.
journal_name
Bioorg Med Chemjournal_title
Bioorganic & medicinal chemistryauthors
Gangjee A,Namjoshi OA,Yu J,Ihnat MA,Thorpe JE,Bailey-Downs LCdoi
10.1016/j.bmc.2012.12.045subject
Has Abstractpub_date
2013-03-01 00:00:00pages
1312-23issue
5eissn
0968-0896issn
1464-3391pii
S0968-0896(13)00022-9journal_volume
21pub_type
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