Design,Synthesis,and Activity Study Of Novel Potential B-Raf Inhibitors And Synthesis Of Epibatidine

This Thesis consists of three parts:(1) Design, synthesis and biological activity study of novel potential B-Raf inhibitors; (2) Synthesis of Epibatidine; (3) Synthesis of 2-aminothiophenes via imidazole-catalyzed Gewald reaction.Chapter I:This project used non-activated conformation of B-Raf mutant (V600E, PDB ID: 1UWJ) as protein model. The initial screening of molecular library containing around 120,000 molecules came from SPECS was under taken in Glide SP docking. The next level of virtual screening was concentrated on the pharmacophore. And finally, some poor drug-likeness molecules were removed. As a result, the 66 commercial compounds were tested and five of them were found to haveμmol/L-level activity on cellular level. Taking into account that compound 33 had good activity on both cells and enzymes together with its inhibition rate of the wild-type B-Raf was lower than it of the mutant type, we chose it as the leading compound of the B-Raf inhibitor for the further structure optimization. Three categories of the designed compounds (A1-25, B1-20, C1-27) were synthesized and tested. Six compounds had an IC50 value better than that of the lead compound on A375 cell. This part of the research provided good leading structures for the development of anti-melanoma drugs with independent intellectual property right.Chapter II:This work started with 6-chloronicotinaldehyde. edno-Epibatidine was obtained after six steps including Herny reaction, intramolecular Michael addition etc. L-Proline catalyzed asymmetric intermolecular Michael addition was used to convert compound 57 into 56 with two chiral centers. This reaction has high diastereoselectivity (dr>20:1). Then,56 passed TarB-H/NaBH4 asymmetric reduction followed by the intermolecular cyclization to gave endo-Epibatidine total yield 27%. The synthetic route was quite simple and convenient. This project not only enriched the practical work of the total synthesis of Epibatidine but also provided a useful guide for the designing the synthesis route for Epibatidine.Chapter III:A facile and practical new method for the synthesis of multisubstituted 2-aminothiophenes in moderate to good yields through the reaction of aldehydes, or ketones with dicyanomethane and elemental sulfur in DMF in the presence of catalytic amount of imidazole was described. This method has the advantage of mild condition, high yield and good regioselectivity.