Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.
We designed, synthesized and evaluated 13 novel tricyclic indeno[2,1-d]pyrimidines as RTK inhibitors. These analogues were synthesized via a Dieckmann condensation of 1,2-phenylenediacetonitrile followed by cyclocondensation with guanidine carbonate to afford the 2-amino-3,9-dihydro-indeno[2,1-d]pyrimidin-4-one. Sulfonation of the 4-position followed by displacement with appropriately substituted anilines afforded the target compounds. These compounds were potent inhibitors of platelet-derived growth factor receptor β (PDGFRβ) and inhibited angiogenesis in the chicken embryo chorioallantonic membrane (CAM) assay compared to standards. In addition, compound 7 had a two digit nanomolar GI(50) against nine tumor cell lines, a submicromolar GI(50) against 29 of other tumor cell lines in the preclinical NCI 60 tumor cell line panel. Compound 7 also demonstrated significant in vivo inhibition of tumor growth and angiogenesis in a B16-F10 syngeneic mouse melanoma model.
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, United States. gangjee@duq.edu
Aleem
A
Gangjee
Ying
Y
Zhao
Michael A
MA
Ihnat
Jessica E
JE
Thorpe
Lora C
LC
Bailey-Downs
Roy L
RL
Kisliuk
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; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007192:Indenes / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D008546:Melanoma, Experimental / Q000188:drug therapy; D051379:Mice; D011743:Pyrimidines / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism
C575841:(4-chlorophenyl)-9H-indeno(2,1-d)pyrimidine-2,4-diamine; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D007192:Indenes; D011743:Pyrimidines; D020797:Receptor, Platelet-Derived Growth Factor beta