Mahboobi, Siavosh and Uecker, A. and Cénac, C. and Sellmer, A. and Eichhorn, E. and Elz, Sigurd and Böhmer, F.-D. and Dove, Stefan (2007) Inhibition of FLT3 and PDGFR tyrosine kinase activity by bis(benzo[b]furan-2-yl)methanones. Bioorganic & medicinal chemistry 15 (5), pp. 2187-2197.
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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 deriv. The 5,5'-diamino and the 6,6'-dihydroxy compds. are more active at FLT3. At both kinases, the potency of the best inhibitors approaches IC50 values of .apprx.0.5 mM. Mol. modeling studies suggest that the bisbenzofuranylmethanones are able to fit into the same binding site as their indolyl analogs 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.
|Institutions:|| Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz)
|Projects:||Deutsche Krebshilfe 10-2100|
|Subjects:||500 Science > 570 Life sciences|
500 Science > 540 Chemistry & allied sciences
600 Technology > 610 Medical sciences Medicine
|Refereed:||Yes, this version has been refereed|
|Created at the University of Regensburg:||Partially|
|Owner:||Prof. Dr. Stefan Dove|
|Deposited On:||20 Jan 2009 16:38|
|Last Modified:||05 Aug 2009 13:50|