Herein,we reported the stereodivergent synthesis of C-glycosamino acids via Pd/Cu dual catalysis and found a suitable system to resolve many challenges,such as the tolerance towards the density of functional groups,th...Herein,we reported the stereodivergent synthesis of C-glycosamino acids via Pd/Cu dual catalysis and found a suitable system to resolve many challenges,such as the tolerance towards the density of functional groups,the variability of the anomeric position,the compatibility of appropriate catalyst combinations,the regioselectivity of nucleophiles,and the match/mismatch problems between chiral substrates and chiral ligand-metal complexes.The method enables the efficient preparation of a series of unnatural C-glycosamino acid skeletons bearing two contiguous stereogenic centers in good yields with excellent diastereoselectivity.From this crucial precursor,various C-glycosamino acid derivatives have been achieved diversely.The readily prepared C-glycosamino acid hybrids will meet the growing demands for the development of new molecular entities for discovering new drugs and materials.This stereodivergent synthesis of C-glycosamino acids will further accelerate the study of their structural features,mode of action,and potential biological applications in the near future.展开更多
E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewisx(...E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewisx(sLex).Efficient leukocyte recruitment under vascular flow conditions depends on an increased lifetime of E-selectin/ligand complexes under tensile force in a so-called catch-bond binding mode.Co-crystal structures of a representative fragment of the extracellular E-selectin region with sLex and a glycomimetic antagonist thereof reveal an extended E-selectin conformation,which is identified as a high-affinity binding state of E-selectin by molecular dynamics simulations.Small-angle X-ray scattering experiments demonstrate a direct link between ligand binding and E-selectin conformational transition under static conditions in solution.This permits tracing a series of concerted structural changes connecting ligand binding to conformational stretching as the structural basis of E-selectin catch-bond-mediated leukocyte recruitment.The detailed molecular view of the binding site paves the way for the design of a new generation of selectin antagonists.This is of special interest,since their therapeutic potentialwas recently demonstrated with the pan-selectin antagonists GMI-1070(Rivipansel).展开更多
基金supported by the National Natural Science Foundation of China(051170001,21772084,22071087)the Fundamental Research Funds for the Central Universities(lzujbky-2017k06)+1 种基金the Open Projects Funds of Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology,Shandong University(2019CCG05)Xiaolei Wang thanks the Thousand Young Talents Program for financial support。
文摘Herein,we reported the stereodivergent synthesis of C-glycosamino acids via Pd/Cu dual catalysis and found a suitable system to resolve many challenges,such as the tolerance towards the density of functional groups,the variability of the anomeric position,the compatibility of appropriate catalyst combinations,the regioselectivity of nucleophiles,and the match/mismatch problems between chiral substrates and chiral ligand-metal complexes.The method enables the efficient preparation of a series of unnatural C-glycosamino acid skeletons bearing two contiguous stereogenic centers in good yields with excellent diastereoselectivity.From this crucial precursor,various C-glycosamino acid derivatives have been achieved diversely.The readily prepared C-glycosamino acid hybrids will meet the growing demands for the development of new molecular entities for discovering new drugs and materials.This stereodivergent synthesis of C-glycosamino acids will further accelerate the study of their structural features,mode of action,and potential biological applications in the near future.
基金supported by the Swiss National Science Foundation(grant number 200020_129935 and R’EQUIP 145023).
文摘E-selectin is a cell-adhesion molecule of the vascular endothelium that promotes essential leukocyte rolling in the early inflammatory response by binding to glycoproteins containing the tetrasaccharide sialyl Lewisx(sLex).Efficient leukocyte recruitment under vascular flow conditions depends on an increased lifetime of E-selectin/ligand complexes under tensile force in a so-called catch-bond binding mode.Co-crystal structures of a representative fragment of the extracellular E-selectin region with sLex and a glycomimetic antagonist thereof reveal an extended E-selectin conformation,which is identified as a high-affinity binding state of E-selectin by molecular dynamics simulations.Small-angle X-ray scattering experiments demonstrate a direct link between ligand binding and E-selectin conformational transition under static conditions in solution.This permits tracing a series of concerted structural changes connecting ligand binding to conformational stretching as the structural basis of E-selectin catch-bond-mediated leukocyte recruitment.The detailed molecular view of the binding site paves the way for the design of a new generation of selectin antagonists.This is of special interest,since their therapeutic potentialwas recently demonstrated with the pan-selectin antagonists GMI-1070(Rivipansel).