Design,synthesis,and Structure-activity-relationship Of Tetrahydroquinoline Derivatives As CXCR4 Small Molecule Inhibitors

Chemokines are a class of small molecule secreted proteins with chemotactic effects,composed of 70 to 100 amino acids.They are divided into four subgroups of CXC,CC,C and CX3C according to the position and quantity of the cysteine residues.The chemokine receptor is also divided into four subgroups according to the type of chemokine it binds(CXCR,CCR,CR,CX3CR).CXCR4 belongs to the CXCR class of chemokine receptors and its natural ligand is CXCL12(also known as SDF-1?).CXCL12/CXCR4 axis is involved in some important physiological processes.When it's activated normally,it can regulate cell growth,development and migration.However,when it's activated abnormally,it's associated with pathologies.AMD3100 is the only small molecule CXCR4 inhibitor approved for mobilizing hematopoietic stem cells of non-Hodgkin's lymphoma and multiple myeloma.AMD070 is currently in clinical phase?/? for the treatment of WHIM syndrome.This paper mainly adopts the strategies of scaffold hybridization and cyclization to optimize the structure which was obtained in our laboratory to find compounds with novel structure and better activity.These strategies optimized to get total 42 compounds.Compound 13 and 36 demonstrate excellent binding affinity with CXCR4 receptor(13:IC50=8.8 nM,36:IC50=24 nM)and inhibit CXCL12 induced cytosolic calcium increase(13:IC50=0.02 nM,36:IC50=0.12 nM).Futhermore,compound 13 shows acceptable CYP inhibition(3A4:48%,2D6:57%)and compound 36 has a good inhibition of cell migration.