title: Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones.
abstract: A series of bis(benzo[b]furan-2-yl)methanones was synthesized and tested for inhibition of FLT3 and PDGFR autophosphorylation. Mostly, C-5 substitution leads to PDGFR selectivity, which was strongest in the case of the 5,5'-dimethoxy derivative. The 5,5'-diamino and the 6,6'-dihydroxy compounds are more active at FLT3. At both kinases, the potency of the best inhibitors approaches IC50 values of ca. 0.5 microM. Molecular modeling studies suggest that the bisbenzofuranylmethanones are able to fit into the same binding site as their indolyl analogues which have been suggested to form a bidentate hydrogen bridge with the backbone in the hinge regions. The loss of one H bond by the NH-O exchange might be partially compensated by, for example, the weak interaction of one furanyl oxygen with FLT3 Cys-828.
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, D-93040 Regensburg, Germany. siavosh.mahboobi@chemie.uni-regensburg.de
authors.forename: Siavosh
authors.initials: S
authors.lastname: Mahboobi
authors.forename: Andrea
authors.initials: A
authors.lastname: Uecker
authors.forename: Christophe
authors.initials: C
authors.lastname: Cénac
authors.forename: Andreas
authors.initials: A
authors.lastname: Sellmer
authors.forename: Emerich
authors.initials: E
authors.lastname: Eichhorn
authors.forename: Sigurd
authors.initials: S
authors.lastname: Elz
authors.forename: Frank-D
authors.initials: FD
authors.lastname: Böhmer
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D005663:Furans; C497971:Flt3 protein, mouse; D017479:Receptors, Platelet-Derived Growth Factor; D051941:fms-Like Tyrosine Kinase 3