Design and Synthesis of Tri-substituted Chiral Pyrrolidin-2-one Derivatives as CCR4 Antagonists

A series of tri-substituted chiral pyrrolidin-2-one derivatives have been designed and synthesized as CC chemokine receptor 4 (CCR4) antagonists. The structure of CCR4 was built by homology modeling. Asymmetric synthesis was applied to synthesize the R,R configuration chiral pyrrolidin-2-one scaffold. The stereoisomeric configurations of the compounds were identified by 2D H-1-H-1 COSY spectroscopy and 1D NOESY spectroscopy. This method was more economical and convenient than traditional X-ray single crystal diffraction. In addition, the interactions between these compounds and the N-terminal extracellular tail of CCR4 were studied using capillary zone electrophoresis. The CCR4 chemotaxis inhibition effect was tested in CCR4-transfected HEK293 cells. Several compounds showed potent activities as CCR4 antagonists. Among these compounds, 1c is the most active one. Its apparent binding constant of CZE experiment result is (1.569 +/- 0.11)x10(5) L<bold></bold>mol(-1), and its percentage inhibition of the HEK293/CCR4 cells migration with the concentration of 1 mu mol<bold></bold>L-1 in DMSO is 59%. And compound 1f has slightly higher affinity to N-terminal of CCR4 according to its apparent binding constant than 1b because of the introduced ester linkage. Further studies on the mechanism of these compounds are in progress.http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000327882900005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=8e1609b174ce4e31116a60747a720701Chemistry, MultidisciplinarySCI(E)中国科学引文数据库(CSCD)4ARTICLE9,SI1144-11523