863223-52-3Relevant academic research and scientific papers
Profile and molecular modeling of 3-(indole-3-yl)-4-(3,4,5- trimethoxyphenyl)-1H-pyrrole-2,5-dione (1) as a highly selective VEGF-R2/3 inhibitor
Peifer, Christian,Krasowski, Agata,H?mmerle, Nina,Kohlbacher, Oliver,Dannhardt, Gerd,Totzke, Frank,Sch?chtele, Christoph,Laufer, Stefan
, p. 7549 - 7553 (2006)
We report on selectivity profiling of 1 in a panel of 20 protein kinases and molecular modeling indicating 1 to be highly active and selective for VEGF-R2/3. Sequence alignment analysis and detailed insights into the ATP binding pockets of targeted protei
Photoactivatable caged prodrugs of VEGFR-2 kinase inhibitors
Pinchuk, Boris,Horbert, Rebecca,D?bber, Alexander,Kuhl, Lydia,Peifer, Christian
, (2016/06/15)
In this study, we report on the design, synthesis, photokinetic properties and in vitro evaluation of photoactivatable caged prodrugs for the receptor tyrosine kinase VEGFR-2. Highly potent VEGFR-2 inhibitors 1 and 3 were caged by introduction of a photoremovable protecting group (PPG) to yield the caged prodrugs 4 and 5. As expected, enzymatic and cellular proliferation assays showed dramatically diminished efficacy of caged prodrugs in vitro. Upon ultraviolet (UV) irradiation of the prodrugs original inhibitory activity was completely restored and even distinctly reinforced, as was the case for the prodrug 4. The presented results are a further evidence for caging technique being an interesting approach in the protein kinase field. It could enable spatial and temporal control for the inhibition of VEGFR-2. The described photoactivatable prodrugs might be highly useful as biological probes for studying the VEGFR-2 signal transduction.
Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers
Ilovich, Ohad,Billauer, Hana,Dotan, Sharon,Mishani, Eyal
experimental part, p. 612 - 620 (2010/05/02)
In a continued effort to find a suitable PET tracer for visualization of angiogenic processes, we explored the 3,4-diarylmaleimide family, known to have high affinity and selectivity towards the VEGFR-TKs. One previously reported agent and three new halogen-containing 3,4-diarylmaleimide derivatives were synthesized. The four maleimide derivatives were evaluated for their affinity and selectivity towards the VEGFRs and exhibited promising results. An automated carbon-11 radiolabeling route with a total synthesis time of 50 min successfully labeled the lead compound, resulting in 1.55 ± 0.15 GBq of tracer with a radiochemical yield of 20 ± 2%, 96% radiochemical purity and a SA of 111 ± 22 GBq/μmol (EOB, n = 5). The tracer possessed high stability in in vitro blood stability tests and specific VEGFR-TK binding profiles in intact cell binding experiments. Tracer lipophilicity was evaluated in an n-octanol/phosphate buffer system giving a Log D7.4 of 1.99 ± 0.04. For the in vivo experiments, two animal models were used. The first was a U87 glioma tumor model, frequently reported in the literature and the second, a newly developed 293/KDR tumor model. Both models were validated for VEGFR-2 expression and used in in vivo biodistribution studies. These studies revealed low accumulation and rapid washout of the tracer from tumor tissue. High accumulation of activity in the liver prompted us to examine the tracer's in vitro stability to liver microsomes, revealing low resistance to P450 metabolism. In spite of encouraging in vitro results, the labeled lead tracer failed to accumulate in VEGFR-2 overexpressing tumors. It is possible that poor resistance to P450 metabolism reduces tracer's circulation leading to low tumor accumulation.
Design, synthesis, and biological evaluation of novel 3-aryl-4-(1H-indole- 3yl)-1,5-dihydro-2H-pyrrole-2-ones as vascular endothelial growth factor receptor (VEGF-R) inhibitors
Peifer, Christian,Selig, Roland,Kinkel, Katrin,Ott, Dimitri,Totzke, Frank,Sch?chtele, Christoph,Heidenreich, Regina,R?cken, Martin,Schollmeyer, Dieter,Laufer, Stefan
experimental part, p. 3814 - 3824 (2009/05/11)
In this study we report on the design, synthesis, and biological evaluation of pyrrole-2-one 2 to be a highly potent VEGF-R2/3 inhibitor with IC 50 of 31/37 nM. The novel 3,4-diaryl-2H-pyrrole-2-ones were designed on the basis of the modeled binding mode of the corresponding 1H-pyrrole-2,5-dione (maleimide) VEGF-R2/3 inhibitor 1 indicating two H-bond ligand-protein interactions in the ATP pocket for the amide 2 but not for the isomer 3. Flexible synthetic routes to 3,4-diaryl-2//-pyrrole-2-ones and structure-activity relationships for the compounds in a panel of 24 therapeutically relevant protein kinases (IC50 values) are presented. Accordingly to the in vitro data, compounds 1 and 2 were found to possess highly potent antiangiogenic activities in the cellular HLMEC sprouting assay and also slightly induced apoptosis in HDMECs whereas 3 was determined to be significantly less active. Hence, the pyrrole-2-one moiety was dissected from the corresponding maleimide protein kinase inhibitor as a suitable key pharmacophore.
Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors
Peifer, Christian,Stoiber, Thomas,Unger, Eberhard,Totzke, Frank,Sch?chtele, Christoph,Marmé, Dieter,Brenk, Ruth,Klebe, Gerhard,Schollmeyer, Dieter,Dannhardt, Gerd
, p. 1271 - 1281 (2007/10/03)
The new analogue 2 of combretastatin A-4 was discovered to be an inhibitor of tubulin polymerization with an IC50 of 7.6 μM and reduced angiogenesis in the in vivo chick embryo model. Interestingly, in a series of 2,3-diarylmaleimides closely r
3-(INDOLYL)-4-ARYLMALEIMIDE DERIVATIVES AND THEIR USE AS ANGIOGENESIS INHIBITORS
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Page/Page column 14-15, (2008/06/13)
The present invention relates to a compound of formula (I) wherein R1 is H, C1-C6-alkyl, phenyl-C1-C4-alkyl or phenyl, R2 is a phenyl group which is substituted with 2 or 3 C1-C
