Study On The Mechanism Of Anti C-Met Activity Of Boc-Protected Amino Groups Of Bithiazolophanes By Using Silcs

We have synthesized some bithiazolophane derivatives and analyzed inhibitory activity against protein kinases, including c-Mets. Only 2,15-Bis(tert-butoxycarbonyl)-2,15-diaza[3.3](2,2’)(4,4’-bithiazolophane) (BOCBTP) showed anti-c-Met activity (IC50 = 603 nm) among the bithiazolophane analogs. When we changed the tert-butoxy groups in this compound into iso-butoxy groups, the anti-c-Met activity of this compound diminished. To understand why only BOCBTP showed anti-c-Met activity, we applied a computational simulation method: Site-Identification by Ligand Competitive Saturation (SILCS) and c-Mets X-ray crystal structures with bound ligands. Characterization and identification of the binding site of our compounds was performed using docking simulation in SILCS. Based on X-ray crystal structures one main active site in c-Mets was identified, which can accept two types of ligands, bent or long straight ligands. Both these ligands have the following interactions; hydrophobic interaction, hydrogen bond and π-π stacking. As SILCS simulation also showed the hydrophobic and some hydrophilic areas in the same site, the results confirmed the active site of c-Met. Our compounds were also placed at a possible alternative binding site identified by SILCS. When our compounds were docked into the site, only one side chain placed there and basic skeleton was out of the pocket. Although BOCBTP also placed at same position, BOC groups of BOCBTP located near aspartic acid residues. If two BOC groups will be cleaved with protons of aspartic acid, the steric shape of BOCBTP would change into a flat shape. As the flat shape of BOCBTP derivatives can enter into the active site deeply, it is hypothesized that this is the reason only BOCBTP showed anti-c-Mets activity.