title: Synthesis and biological evaluation of tyrosine modified analogues of the α4β7 integrin inhibitor biotin-R₈ERY.
abstract: The α4β7 integrin is a well-known target for the development of drugs against various inflammatory disease states including inflammatory bowel disease, type 1 diabetes and multiple sclerosis. The synthesis of a small library of cell-permeable β7 integrin inhibitors based on the peptide biotin-R(8)ERY is reported, in which the tyrosine residue has been modified by using the Suzuki-Miyaura cross-coupling reaction. The synthesised peptidomimetics were evaluated in a cell adhesion assay and shown to inhibit Mn(2+)-activated adhesion of mouse TK-1 T cells to mouse MAdCAM-1. All of the synthesised peptidomimetics are more active than our previously reported lead compound biotin-R(8)ERY with two of the analogues, 6 and 7, exhibiting IC(50) values of <15 μM.
authors.affiliation: School of Chemical Sciences, The University of Auckland, 23 Symonds Street, Auckland Central 1010, New Zealand.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Papst
authors.forename: Anaïs F M
authors.initials: AF
authors.lastname: Noisier
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Brimble
authors.forename: Yi
authors.initials: Y
authors.lastname: Yang
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: Krissansen
mesh_terms: D000818:Animals; D001710:Biotin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D016023:Integrins / Q000037:antagonists & inhibitors*; D008345:Manganese / Q000494:pharmacology; D051379:Mice; D008968:Molecular Conformation; D009088:Mucoproteins; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D015815:Cell Adhesion Molecules; D016023:Integrins; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D009842:Oligopeptides; D057786:Peptidomimetics; D011994:Recombinant Proteins; C071777:integrin alpha4beta7; D014443:Tyrosine; D008345:Manganese; D001710:Biotin