Design, Synthesis, Optimization And Modulating Mechanism Study Of Non Steroidal FXR Ligands And Synthetic Methodology Of Two Kinds Of Privileged Scaffolds

There are two parts in my dissertation for Ph. D. degree. Part 1 presents the design, synthesis, optimization, biological evaluation and modulating mechanism study of non-steroidal FXR ligands.As a member of nuclear receptors, FXR is highly expressed in the liver, intestine, kidney and adrenal glands. So far, FXR has been demonstrated to function as a modulator in the regulation of cholesterol, bile acid, lipid and glucose metabolism. Moreover, the role FXR has been extended into several diseases including cholestasis, atherosclerosis, gall-stone, diabetes and cancers. While most of the FXR ligands with a steroidal scaffold potentially lead to the lack of target selectivity and gene selectivity. Consequently, developing FXR ligands. with non-steroidal scaffold is of great significance for the drug design targeting on FXR. Thus, we discussed the design, synthesis, optimization, biological evaluation and modulating mechanism study of FXR ligands.GW4064 (24, the first reported potent FXR agonist with high NRs selectivity) and the previously reported potent FXR antagonist (18) with high NRs selectivity in our group were used as templates for designing novel non-steroidal FXR ligands on the basis of pharmacophore combination principles. Our lead compound was obtained through reconstruction of 18 and the lyophobic pharmacophore of GW4064 (24). In total,45 compounds (36, A1～19, B1～25) were synthesized after chemical modifications of three cycles. Three compounds (A10, B2 and B3) were confirmed as FXR agonists and one compound (B25) as FXR antagonist according to the molecular-based and cell-based assay. Consequently, B25 was selected to study the antagonistic mechanism of FXR via molecular dynamic simulation. The binding of B25 to FXR led to the conformation changes of HI2, which prevented the recruitment of coactivator. Our molecular modeling results proposed the essential molecular bases of FXR antagonism which were consistent with the previously reported mechanism, and elucidated that the conformation of E467 on H12 plays an important role in the FXR antagonism.Part 2 concerns the synthetic methodology of two "priviledged scaffold". Two kinds of 3-substituted-indolin-2-one scaffold were synthesized with benzophenone imine as key starting material. We could construct priviledged scaffold with more efficient way for supplying highly synthetic useful building blocksWe have developed the first synthetic method of unprotected unnatural amino-acids containing 3-hydroxyoxindole skeleton. Employing substituted isatins (56),/-butyl 2-aminoacetate hydrochloride (57) and benzophenone imine (58) as starting materials, we synthesized unprotected unnatural amino-acids containing 3-hydroxyoxindole via a three-component reaction in good to excellent yields (58-90%).We have also develop the amination of aldehydes, diarylmethanes and 3-substituted-indoline-2-one via oxidative reactions. Employing benzophenone imine (58) as starting material, we obtained the rarely reported primary amine product under the iodine/TBHP catalytic system in moderate to excellent yields (38-89%).In summary, based on the pharmacophore combination principles,45 compounds (36, A1～19,B1～25) were designed and synthesized targeting FXR. Four FXR non-steroidal ligands were found, among them one antagonist were employed in the molecular dynamic simulation for elucidating the molecular mechanism of FXR antagonism. Two kinds of synthetic methodology for constructing two kinds of 3-substituted-indoline-2-one were probed employing benzophenone iminc (58) as key starting material, These researches provided some new templates to discover new chemical entities for drug development.