N2-Trimethylacetyl substituted and unsubstituted-N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines: Design, cellular receptor tyrosine kinase inhibitory activities and in vivo evaluation as antiangiogenic, antimetastatic and antitumor agents

Six novel N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines and their N2-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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2013-03, Vol.21 (5), p.1312-1323
Main Authors: Gangjee, Aleem, Namjoshi, Ojas A., Yu, Jianming, Ihnat, Michael A., Thorpe, Jessica E., Bailey-Downs, Lora C.
Format: Article
Language:English
Subjects:
Angiogenesis Inhibitors - chemistry
Angiogenesis Inhibitors - therapeutic use
Angiogenesis Inhibitors - toxicity
Animals
Antiangiogenic
Antimetastatic
antineoplastic agents
Antineoplastic Agents - chemistry
Antineoplastic Agents - therapeutic use
Antineoplastic Agents - toxicity
Cell Line, Tumor
Cell Survival - drug effects
cytotoxicity
Disease Models, Animal
Drug Design
Humans
hydrophobicity
In vivo
in vivo studies
Melanoma, Experimental - drug therapy
metastasis
Mice
Mice, Nude
Microwaves
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - therapeutic use
Protein Kinase Inhibitors - toxicity
Pyrimidines - chemistry
Pyrimidines - therapeutic use
Pyrimidines - toxicity
Pyrroles - chemistry
Pyrroles - therapeutic use
Pyrroles - toxicity
receptor protein-tyrosine kinase
Receptor Protein-Tyrosine Kinases - antagonists & inhibitors
Receptor Protein-Tyrosine Kinases - metabolism
Sonogashira coupling
Structure-Activity Relationship
tyrosine
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Summary:Six novel N4-phenylsubstituted-6-(2-pyridin-2-ylethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines and their N2-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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.12.045