5-CHLORO-3-[(3,5-DIMETHYLPYRROL-2-YL)METHYLENE]-2-INDOLINONE

Uses

SU5614 is a FMS-like tyrosine kinase 3 (FLT3) inhibitor; selective inhibitor of VEGF and PDGF receptor tyrosine kinases.

Definition

ChEBI: SU5614 is a member of the class of oxindoles that is 5-chlorooxindole in which the two hydrogens at position 3 are replaced by a (3,5-dimethylpyrrol-2-yl)methylidene group. It has a role as a vascular endothelial growth factor receptor antagonist. It is a member of pyrroles, a member of oxindoles and an organochlorine compound.

Biological Activity

su5614 is a protein tyrosine kinase inhibitor.tyrosine kinases are enzymes for the activation of many proteins by signal transduction cascades. the proteins are activated by adding a phosphate group to the protein.

Synthesis

The general procedure for the synthesis of (Z)-5-chloro-3-((3,5-dimethyl-1H-pyrrol-2-ylidene)methylene)indolin-2-one from 3,5-dimethyl-2-pyrrolecarboxaldehyde and 5-chloroindole oxide was as follows: 5-chloroindole oxide (6.98 g, 41.6 mmol), 3,5-dimethyl-1H-pyrrole-2-carboxaldehyde (5.12 g 41.6 mmol) and piperidine (410 μL, 4.16 mmol) were dissolved in 200 mL of ethanol and heated to reflux for 8 hours. After completion of the reaction, the mixture was cooled to room temperature and the solid was collected by filtration to afford the target product (Z)-5-chloro-3-((3,5-dimethyl-1H-pyrrol-2-yl)methylene)indolin-2-one (4.50 g, 40% yield) as a red to orange solid.

in vitro

previous study found that su5614 could induce growth arrest and apoptosis in c-kit-expressing kasumi-1, m-07e, and ut-7 cells and inhibited the stem cell factor (scf)-induced tyrosine phosphorylation of c-kit. moreover, the sensitivity of kasumi-1 cells towards the growth inhibitory activity of su5614 was mainly caused by an autocrine production of scf, but not by the transforming mutations of c-kit [1].

in vivo

it was found that administration of su5614, a vascular endothelial growth factor (vegf) inhibitor, to mice could reduce the levels of vegf dramatically in bal fluids 72 h after toluene diisocyanate inhalation. moreover, consistent with the results obtained from the enzyme immunoassays, western blot analyses showed that su5614 reduced the levels of vegf in the bal fluid 72 h after toluene diisocyanate inhalation. these results suggested that vegf might be one of the major determinants of toluene diisocyanate -induced asthma and that the inhibition of vegf might be a good therapeutic strategy [2].

IC 50

100 nm for flt3 inhibition

References

[1] spiekermann k,faber f,voswinckel r,hiddemann w. the protein tyrosine kinase inhibitor su5614 inhibits vegf-induced endothelial cell sprouting and induces growth arrest and apoptosis by inhibition of c-kit in aml cells. exp hematol.2002 jul;30(7):767-73.
[2] lee yc,kwak yg,song ch. contribution of vascular endothelial growth factor to airway hyperresponsiveness and inflammation in a murine model of toluene diisocyanate-induced asthma. j immunol.2002 apr 1;168(7):3595-600.