| Privileged structure was first addressed by Evans et al.in1988, which was defined as a single molecular framework able to provide ligands for diverse receptors, and was improved by Patchett and Nargund in2000:providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications. This structures have lead compounds and Drug-like properties. The design of new chemical molecules libraries for bioassays based on some privileged structures has attracted many medicinal chemists so far. This dissertation was mainly focused on synthetic methodology study of thienopyrimidines and design libraries based on a diversity-oriented synthesis approach, and evaluations on biological activities.Thienopyrimidines nuclei is a typical privileged structures and many types of biologically active compounds bear this framework. Based on our previous work on synthetic methodology study on selective dechlorination of2,4-dichloropyrimidines, we designed and prepared thienopyrimidines blocks bearing2～3different reacting points as to build up a small molecule library original material. Through nucleophilic substitution and Suzuki coupling reaction, based on a diversity-oriented synthesis approach, we finished the construction of library1containing130compounds. At first, library1was evaluated on protein kinase c-Met、Adenosine Receptors A1R and PI3K inhibitors.1) protein kinase c-Met:evaluation results showed that the mostly compounds are not good c-Met inhibitors.2) Adenosine Receptors AIR:at first, we discovered9active compounds on Adenosine Receptors AIR. LXY-67displayed a91.58%inhibition on AIR at a concentration of5μg/mL. Based on LXY-67and guided by preliminary structure-activity relationship, we synthesized focus library2containing11compounds, and found LXY-83, the most potent compound on Adenosine Receptors AIR, displaying a92.37%inhibition at a concentration of5 μg/mL.3) PI3K inhibitor:we discovered5active compounds on PI3K. |
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