A development of chimeric VEGFR2 TK inhibitor based on two ligand conformers from PDB: 1Y6A complex--medicinal chemistry consequences of a TKs analysis.

VEGFR2 is an important mediator of angiogenesis and influences fate of some cancer stem cells. Here we analysed all 34 structures of VEGFR2 TK available from PDB database. From them a complex PDB: 1Y6A has an exceptional AAZ ligand bound to TK in form of two conformers (U- and S-shaped). This observation inspired us to develop three chimeric bispyridyl VEGFR2 inhibitors by combining structural features of both AAZ conformers and/or their relative ligand AAX (PDB: 1Y6B). Our most interesting inhibitor 22SYM has an enzymatic VEGFR2 TK activity (IC50: 15.1 nM) comparable or better to the active compounds from clinical drugs Nexavar and Sutent. 22SYM inhibits growth, migration and tube formation of endothelial cells (EC) and selectively induces EC apoptosis. 22SYM also inhibits in vivo angiogenesis in Zebrafish embryo assay. Additionally to the above results, we proved here that tyrosine kinases in an inactive form possessing Type I inhibitors can adopt both a closed or an opened conformation of kinase A-loop independently on their DFG-out arrangement. We proposed here that an activity of certain Type I inhibitors (e.g. 22SYM-like) in complex with DFG-out TK can be negatively influenced by collisions with a dynamically moving TK A-loop.

New 1,3-oxathianes derived from myrtenal: synthesis and reactivity.

2-Methyl- and 2-phenyl-substituted oxathianes derived from Myrtenal have been synthesized in satisfying yields. Lithiation of 2-methyl-substituted oxathiane could not be done, but lithiation of 2-phenyl-substituted and non-substituted oxathianes could be performed with s-BuLi. Quenching with D(2)O, TMSCl, and/or a carbonyl compound always provides the equatorial product in consistency with a prefered equatorial orientation of the lithium in the lithiated derivatives. A model is proposed to rationalize the diastereoselectivities observed at C5' during reaction of aldehydes with lithiated non-substituted oxathiane. The model is based on the hypothesis that the lithium, being linked simultaneously to the carbon and the oxygen, is shifted toward the oxygen side, making the steric hindrance of this side more effective. Dimeric side products were observed during formation of these oxathianes (condensation of various aldehydes with the corresponding hydroxythiol), which had not been reported for other oxathianes (derived from pulegone and/or camphorsulfonic acid).