20 research outputs found
Structural Basis for Inhibition of Eg5 by Dihydropyrimidines: Stereoselectivity of Antimitotic Inhibitors Enastron, Dimethylenastron and Fluorastrol
Human kinesin Eg5, which plays an essential role in mitosis by establishing the bipolar spindle, has proven to be an interesting drug target for the development of cancer chemotherapeutics. Here, we report the crystal structures of the Eg5 motor domain complexed with enastron, dimethylenastron, and fluorastrol. By comparing these structures to that of monastrol and mon-97, we identified the main reasons for increased potency of these new inhibitors, namely the better fit of the ligand to the allosteric binding site and the addition of fluorine atoms. We also noticed preferential binding of the S-enantiomer of enastron and dimethylenastron to Eg5, while the R-enantiomer of fluorastrol binds preferentially to Eg5. In addition, we performed a multidrug resistance (MDR) study in cell lines overexpressing P-glycoprotein (Pgp). We showed that one of these inhibitors may have the potential to overcome susceptibility to this efflux pump and hence overcome common resistance associated with tubulin-targeting drugs
sp3 CâH Bond Functionalization with Ruthenium Catalysts
International audienceThe selective formation of carbonâcarbon bond by functionalization of an sp3CâH bond is still a challenge in organic synthesis. There are already examples involving transition metal catalysis. In this chapter we review the use of ruthenium(0) and ruthenium(II) catalysts for the formation of carbonâcarbon bonds based on creation of reactive sites by sp3CâH bond activation. We show that in most cases, regioselective sp3CâH bond activation is induced either from functional substrates bearing a directing group, which strongly coordinates the metal centre, or by selective CâH bond activation at the α-carbon of a heteroatom accompanied by hydrogen transfer processes and transient creation of reactive functional group