Synthesis of [1, 2, 4]-Triazines as Kinase Inhibitors and of Novel Fluorine Capture Reagents for PET Probes.

摘要

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor, which plays a pivotal part in the development of the central nervous system. Aberrant expression of full-length ALK occurs in neuroblastoma and chromosomal translocation or inversion of the ALK gene can generate novel fusion-ALK proteins that possess constitutive kinase activity and contribute to oncogenic processes. One of the well-studied fusion proteins is nucleophosmin (NPM-ALK), which draws a lot of attention for medicinal chemists to design small molecules as kinase inhibitors for this target. In this dissertation, [1, 2, 4]-Dihydrotriazine dimers as competitors of the lead compound NVP-TAE684 targeting NPM-ALK have been designed and synthesized. Molecular modelling studies show that those dihydrotriazine dimers have a great potential to be better kinase inhibitors.;Chapter two describes imaging in the drug discovery and development arena. One of important imaging techniques is positron emission tomography (PET). PET is a radionuclide based molecular imaging technique, which can be used for early detection, characterization, "real time" monitoring of diseases, and investigation of the efficacy of drugs. Fluorine-18 (18F) based molecular probes for PET imaging still remain big challenging to prepare but have gained increased interest by radiochemists in the past two decades. In this study, a novel approach to introduce fluorine into a molecular probe has been discovered based on boron chemistry. A few novel fluorine capture reagents have been synthesized and described in this Chapter.