Synthesis and biological activity of N(4)-phenylsubstituted-6-(2,4-dichloro phenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines as vascular endothelial growth factor receptor-2 inhibitors and antiangiogenic and antitumor agents.
A series of eight N(4)-phenylsubstituted-6-(2,4-dichlorophenylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines 8-15 were synthesized as vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors with varied substitutions in the phenyl ring of the 4-anilino moiety. In addition, five N(4)-phenylsubstituted-6-phenylmethylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines 16-20 were synthesized to evaluate the importance of the 2-NH(2) moiety for multiple receptor tyrosine kinase (RTK) inhibition. Cyclocondensation of alpha-halomethylbenzylketones with 2,6-diamino-4-hydroxypyrimidine afforded 2-amino-6-(2,4-dichlorophenylmethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one, 23 and reaction of alpha-bromomethylbenzylketones with ethylamidinoacetate followed by cyclocondensation with formamide afforded the 6-phenylmethylsubstituted-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-ones, 40-42, respectively. Chlorination of the 4-position and displacement with appropriate anilines afforded the target compounds 8-20. Compounds 8, 10 and 14 were potent VEGFR-2 inhibitors and were 100-fold, 40-fold and 8-fold more potent than the standard semaxanib, respectively. Previously synthesized multiple RTK inhibitor, 5 and the VEGFR-2 inhibitor 8 from this study, were chosen for further evaluation in a mouse orthotopic model of melanoma and showed significant inhibition of tumor growth, angiogenesis and metastasis.
Gangjee
Aleem
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, PA 15282, USA. gangjee@duq.edu
Kurup
Sonali
S
Ihnat
Michael A
MA
Thorpe
Jessica E
JE
Shenoy
Satyendra S
SS
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D003959:Diamines / Q000138:chemical synthesis* / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000517:prevention & control; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003959:Diamines; D007211:Indoles; D011743:Pyrimidines; D011744:Pyrimidinones; D011758:Pyrroles; C108140:4-hydroxypyrimidine; C116890:Semaxinib; D040301:Vascular Endothelial Growth Factor Receptor-2
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