title: N⁴-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: design, synthesis, and in vivo evaluation.
abstract: With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).
authors.affiliation: Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA. gangjee@duq.edu
authors.forename: Aleem
authors.initials: A
authors.lastname: Gangjee
authors.forename: Nilesh
authors.initials: N
authors.lastname: Zaware
authors.forename: Sudhir
authors.initials: S
authors.lastname: Raghavan
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Thorpe
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ihnat
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy; D000078183:Oxindoles; D011422:Propionates / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D000078183:Oxindoles; D011422:Propionates; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C450639:Pyrrolo(2,3-d)pyrimidine; C412603:orantinib; D020797:Receptor, Platelet-Derived Growth Factor beta; D040301:Vascular Endothelial Growth Factor Receptor-2