Synthesis of 3‐Alkyl‐5‐arylamino‐6,11‐dihydro‐3H‐anthra[1,2‐d] [1,2,3]triazole‐6,11‐dione 2‐Oxides by Nitrosation of 3‐Alkylamino‐5‐arylamino‐6H‐anthra[1,9‐cd]isoxazol‐6‐ones.

Gornostaev, L. M.; Dolgushina, L. V.; Titova, N. G.; Arnol'd, E. V.; Lavrikova, T. I.

doi:10.1002/chin.200709131

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“…Mass spectrometry and 1 H and 13 C NMR confirmed purity and also the structures of IPR-456 and IPR-803. The 1 H spectra show the characteristic resonance for the intramolecularly hydrogen-bonded NH (to the adjacent carbonyl) at δ 11.79 and for the 4-CH methine at δ 6.12, consistent with literature values (43):…”

Section: Methodssupporting

confidence: 90%

Targeting Multiple Conformations Leads to Small Molecule Inhibitors of the uPAR·uPA Protein–Protein Interaction That Block Cancer Cell Invasion

et al. 2011

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Interaction of the urokinase receptor (uPAR) with its binding partners including the urokinase-type plasminogen activator (uPA) at the cell surface triggers a series of proteolytic and signaling events that promote invasion and metastasis. Here, we report the discovery of a small molecule (IPR-456) and its derivatives that inhibit the tight uPAR·uPA protein-protein interaction. IPR-456 was discovered by virtual screening against multiple conformations of uPAR sampled from explicit-solvent molecular dynamics simulations. Biochemical characterization reveal that the compound binds to uPAR with sub-micromolar affinity (Kd = 310 nM) and inhibits the tight protein-protein interaction with an IC50 of 10 μM. Free energy calculations based on explicit-solvent molecular dynamics simulations suggested the importance of a carboxylate moiety on IPR-456, which was confirmed by the activity of several derivatives including IPR-803. Immunofluorescence imaging showed that IPR-456 inhibited uPA binding to uPAR of breast MDA-MB-231 tumor cells with an IC50 of 8 μM. The compounds blocked MDA-MB-231 cell invasion, but IPR-456 showed little effect on MDA-MB-231 migration, and no effect on adhesion, suggesting that uPAR mediates these processes through its other binding partners.

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Section: Methodssupporting

confidence: 90%

Targeting Multiple Conformations Leads to Small Molecule Inhibitors of the uPAR·uPA Protein–Protein Interaction That Block Cancer Cell Invasion

et al. 2011

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Synthesis of 3‐Alkyl‐5‐arylamino‐6,11‐dihydro‐3H‐anthra[1,2‐d] [1,2,3]triazole‐6,11‐dione 2‐Oxides by Nitrosation of 3‐Alkylamino‐5‐arylamino‐6H‐anthra[1,9‐cd]isoxazol‐6‐ones.

Abstract: Synthesis of 3-Alkyl-5-arylamino-6,11-dihydro-3H-anthra[1,2-d][1,2,3]triazole-6,11-dione 2-Oxides by Nitrosation of 3-Alkylamino-5-arylamino-6H-anthra[1,9-cd]isoxazol-6-ones. -(GORNOSTAEV, L. M.; DOLGUSHINA, L. V.; TITOVA, N. G.; ARNOL'D, E. V.; LAVRIKOVA, T. I.; Russ.

Cited by 1 publication

References 1 publication

Targeting Multiple Conformations Leads to Small Molecule Inhibitors of the uPAR·uPA Protein–Protein Interaction That Block Cancer Cell Invasion

Targeting Multiple Conformations Leads to Small Molecule Inhibitors of the uPAR·uPA Protein–Protein Interaction That Block Cancer Cell Invasion

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