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:10.1134/s1070428006090193

Cited by 5 publications

(3 citation statements)

References 3 publications

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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:…”

Section: Methodssupporting

confidence: 89%

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: 89%

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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“…A second amination was carried out at the 3-position using refluxing acetonitrile to give a moderate yield of 3. 27 Next, hydrolysis of the benzoate ester 3 to the carboxylic acid 4 occurred under conditions of heating an aqueous solution of sodium hydroxide and methanol.…”

Section: Resultsmentioning

confidence: 99%

“…As determined by TLC the reaction was complete after 3 h afterwards the reaction mixture was cooled to ambient temperature then to −15 °C for 1 h. The reddish solid was filtered off and washed with cold acetonitrile to give 52 mg (50%) of 3 . 27 1 H NMR (500 MHz, CDCl 3 ) δ 11.94 (s, 1H-NH), 8.63 (d, J = 8 Hz, 1H-C5), 8.19-8.14 (m, 2H), 7.91 (d, J = 7 Hz, 1H, H para to amino group), 7.73 (t, J = 7 Hz, 1H-C7), 7.64 (t, J = 8 Hz, 1H-C6), 7.58-7.50 (m, 2H), 6.18 (s, 1H), 4.51-3.40 (vbr s, 4H), 3.94 (s, 3H-OMe), 1.91 (br s, 4H), 1.65 (br s, 4H). 13 C NMR (126 MHz, CDCl 3 ) δ 176.0, 166.3, 154.7, 153.6, 148.0, 146.7, 139.1, 133.5, 131.4, 130.6, 129.7, 127.9, 127.7, 126.2, 124.2, 121.8, 118.9, 96.2, 91.9, 52.3, 26.6, 18.9.…”

Section: Methodsmentioning

confidence: 99%

Small-molecule inhibition of the uPAR·uPA interaction: Synthesis, biochemical, cellular, in vivo pharmacokinetics and efficacy studies in breast cancer metastasis

Mani

Wang

Knabe

et al. 2013

Bioorganic & Medicinal Chemistry

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The uPAR·uPA protein-protein interaction (PPI) is involved in signaling and proteolytic events that promote tumor invasion and metastasis. A previous study had identified 4 (IPR-803) from computational screening of a commercial chemical library and shown that the compound inhibited uPAR·uPA PPI in competition biochemical assays and invasion cellular studies. Here, we synthesize 4 to evaluate in vivo pharmacokinetic (PK) and efficacy studies in a murine breast cancer metastasis model. First, we show, using fluorescence polarization and saturation transfer difference (STD) NMR, that 4 binds directly to uPAR with sub-micromolar affinity of 0.2 μM. We show that 4 blocks invasion of breast MDA-MB-231, and inhibits matrix metalloproteinase (MMP) breakdown of the extracellular matrix (ECM). Derivatives of 4 also inhibited MMP activity and blocked invasion in a concentration-dependent manner. 4 also impaired MDA-MB-231 cell adhesion and migration. Extensive in vivo PK studies in NOD-SCID mice revealed a half-life of nearly 5 hours and peak concentration of 5 μM. Similar levels of the inhibitor were detected in tumor tissue up to 10 hours. Female NSG mice inoculated with highly malignant TMD-MDA-MB-231 in their mammary fat pads showed that 4 impaired metastasis to the lungs with only four of the treated mice showing severe or marked metastasis compared to ten for the untreated mice. Compound 4 is a promising template for the development of compounds with enhanced PK parameters and greater efficacy.

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