title: Synthesis and biological evaluation of integrin antagonists containing trans- and cis-2,5-disubstituted THF rings.
abstract: The synthesis of a series of RGD mimetics is described. All compounds consist of a central 2,5-disubstituted tetrahydrofuran core, a variable linker to a guanidino group, and a beta-amino alanine unit to mimic the carboxylic acid. Three types of linkers were investigated: a simple four-atom methylene chain (type A, compounds 14, 15, 16, and 17), a four-atom methylene chain with an additional chiral center, and a nitrogen substituent (type B, compounds 38, 39, and 40), and an amide linker of different length with an additional chiral center (type C, compounds 59, 60, 61, and 62). A variety of compounds were tested as potential integrin antagonists in a receptor binding assay (alphaIIbbeta3, alphavbeta3, and alphavbeta5). The relative and absolute configuration of the chiral centers at the THF ring had a pronounced effect on the binding activity and selectivity. Compound 14 proved to be a selective inhibitor of alphaIIbbeta3 (IC50=20nM), whereas compound 40 exhibited high activity for binding of alphaIIbbeta3 (IC50=67nM) and alphavbeta3 (IC50=52nM).
authors.affiliation: Institut für Chemie der Humboldt-Universität zu Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Osterkamp
authors.forename: B
authors.initials: B
authors.lastname: Ziemer
authors.forename: U
authors.initials: U
authors.lastname: Koert
authors.forename: M
authors.initials: M
authors.lastname: Wiesner
authors.forename: P
authors.initials: P
authors.lastname: Raddatz
authors.forename: S L
authors.initials: SL
authors.lastname: Goodman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D005069:Evaluation Studies as Topic; D005663:Furans / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D016023:Integrins; D009842:Oligopeptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D019030:Receptors, Vitronectin; C018674:tetrahydrofuran; C047981:arginyl-glycyl-aspartic acid