title: Versatile conjugation of octreotide to dendrimers by cycloaddition ("click") chemistry to yield high-affinity multivalent cyclic Peptide dendrimers.
abstract: The somatostatin analogue Tyr(3)-octreotide, which has a high binding affinity for the SSTR2 receptor (somatostatin receptor subtype 2) expressed on tumor cells, is used clinically for the diagnosis and treatment of a variety of neuroendocrine tumors and gastrointestinal disorders. There is growing interest in the development of multivalent peptide systems, because they may have enhanced binding affinity compared to monovalent analogues. In this report, we describe the design and synthesis of a series of Tyr(3)-octreotide-containing monomeric, dimeric, and tetrameric dendrimeric conjugates. These multivalent dendrimeric cyclic peptides were obtained using Cu(I)-catalyzed 1,3-dipolar cycloaddition between peptidyl azides and dendrimeric alkynes. Their affinities for the SSTR2 receptor were determined by a competitive binding assay on rat brain sections.
authors.affiliation: Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.
authors.forename: Cheng-Bin
authors.initials: CB
authors.lastname: Yim
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Monique
authors.initials: M
authors.lastname: de Visser
authors.forename: Marion
authors.initials: M
authors.lastname: de Jong
authors.forename: Annemarie C
authors.initials: AC
authors.lastname: Dechesne
authors.forename: Dirk T S
authors.initials: DT
authors.lastname: Rijkers
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry*; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D003500:Cyclization; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry*; D015282:Octreotide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism*
chemical_list: D000480:Alkynes; D001386:Azides; D050091:Dendrimers; D017481:Receptors, Somatostatin; D003300:Copper; C093733:somatostatin receptor 2; D015282:Octreotide