title: 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.
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.
authors: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu
authors: Aleem
authors: A
authors: Gangjee
authors: Ojas A
authors: OA
authors: Namjoshi
authors: Jianming
authors: J
authors: Yu
authors: Michael A
authors: MA
authors: Ihnat
authors: Jessica E
authors: JE
authors: Thorpe
authors: Lora C
authors: LC
authors: Bailey-Downs
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D008872:Microwaves; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D011758:Pyrroles / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; D020794:Receptor Protein-Tyrosine Kinases
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