title: Influence of chain length on the activity of tripeptidomimetic antagonists for CXC chemokine receptor 4 (CXCR4).
abstract: Here we report a series of close analogues of our recently published scaffold-based tripeptidomimetic CXCR4 antagonists, containing positively charged guanidino groups in R1and R2, and an aromatic group in R3. While contraction/elongation of the guanidine carrying side chains (R1and R2) resulted in loss of activity, introduction of bromine in position 1 on the naphth-2-ylmethyl moiety (R3) resulted in an EC50of 61μM (mixture of diastereoisomers) against wild-type CXCR4; thus, the antagonistic activity of these tripeptidomimetics seems to be amenable to optimization of the aromatic moiety. Moreover, for analogues carrying a naphth-2-ylmethyl substituent, we observed that a Pictet-Spengler like cyclization side reaction depended on the nature of the R1substituent.
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Markus
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Mohammad Musarraf
authors.initials: MM
authors.lastname: Hussain
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Nina
authors.initials: N
authors.lastname: Henne
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Daniel Moya
authors.initials: DM
authors.lastname: Garrote
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Karlshøj
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway.
authors.forename: Torgils
authors.initials: T
authors.lastname: Fossen
authors.affiliation: Laboratory for Molecular Pharmacology, Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen, Denmark.
authors.forename: Mette M
authors.initials: MM
authors.lastname: Rosenkilde
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, Breivika, NO-9037 Tromsø, Norway. Electronic address: jon.vabeno@uit.no.
authors.forename: Jon
authors.initials: J
authors.lastname: Våbenø
authors.affiliation: Department of Chemistry and Centre for Pharmacy, University of Bergen, Allégaten 41, NO-5007 Bergen, Norway. Electronic address: bengt-erik.haug@farm.uib.no.
authors.forename: Bengt Erik
authors.initials: BE
authors.lastname: Haug
mesh_terms: D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001643:Bridged Bicyclo Compounds; C527276:CXCR4 protein, human; D057786:Peptidomimetics; D019718:Receptors, CXCR4
keywords: CXCR4 antagonist; Peptidomimetic; Scaffold