Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

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Gangjee A, Zhao Y, Ihnat MA, Thorpe JE, Bailey-Downs LC, Kisliuk RL

Novel tricyclic indeno[2,1-d]pyrimidines with dual antiangiogenic and cytotoxic activities as potent antitumor agents.

Bioorg Med Chem. 2012 Jul 15;20(14):4217-25. doi: 10.1016/j.bmc.2012.05.068. Epub 2012 Jun 6.

PubMed ID
22739090 [ View in PubMed
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Abstract

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 beta (PDGFRbeta) 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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
10-Propargyl-5,8-Dideazafolic AcidThymidylate synthaseIC 50 (nM)85N/AN/ADetails
ErlotinibEpidermal growth factor receptorIC 50 (nM)1200N/AN/ADetails
MethotrexateDihydrofolate reductaseIC 50 (nM)20N/AN/ADetails
PyrimethamineDihydrofolate reductaseIC 50 (nM)6000N/AN/ADetails
SemaxanibVascular endothelial growth factor receptor 2IC 50 (nM)12900N/AN/ADetails
SunitinibPlatelet-derived growth factor receptor betaIC 50 (nM)83100N/AN/ADetails
SunitinibVascular endothelial growth factor receptor 2IC 50 (nM)18900N/AN/ADetails
TrimethoprimDihydrofolate reductaseIC 50 (nM)>340000N/AN/ADetails