Design, Synthesis And Biological Evaluation Of The Chemokine CXCL12Inhibitor

The chemokine CXCL12and its G protein-coupled receptor (GPCR) CXCR4, which participate in numerous disease states, including tumor metastasis, HIV-1infection, autoimmune disease and cardiovascular disease, are high-priority clinical targets. The CXCL12/CXCR4signaling axis is of increasing interest for drug development, but virtually all drug discovery efforts focus on GPCRs. However, all CXCR4receptor antagonists have unmanageable toxicities, emphasizing the need for alternative strategies to interfere with CXCL12/CXCR4-guided metastatic homing. The first chapter introduces the CXCL12/CXCR4signaling axis, its effect in tumor metastasis, and the inhibitors for antagonizing the CXCL12/CXCR4interaction.In Charpt2, we designed and synthesized85small molecular inhibitors for CXCL12based on the hit compound ZINC310545, which was discovered by Veldkamp et al.. Some of these compounds have been tested for biological activities. And the rest are undergoing in the assay. Till now, we have found several compounds have better affinity and inhibitory activities than the hit compound. Based on the biological activities, we made a conclusion on the SAR of this library, which affords an opportunity for further modification of the structure.Imidazole is a privilege heterocyclic scaffold. This privilege structure is widely present in some significant natural product, major marketed drugs. The range of biological applications led to the focus of imidazole derivations. The chart3presents a one-pot, general approach for the synthesis of disubstituted imidazole via α-azido ketones in situ in the presence of potassium ethylxanthate as a cataslyst.