title: Synthesis and in vitro, ex-vivo and in vivo activity of hybrid compounds linking a potent ROS and RNS scavenger activity with diverse substrates addressed to pass across the blood-brain barrier.
abstract: The synthesis of a small library of CR-6 (a potent ROS and RNS scavenger agent) derivatives bearing covalent linkage with different endogen nutrients that have specific transport through the blood-brain barrier (BBB) is reported. The synthetic sequence involved the preparation of a common precursor ester 6 derived from CR-6, which was easily converted into the carboxylic acid 7a or the amino derivative 11, for its further coupling with the required substrates through amide bonds. Antioxidant in vitro (DPPH) and cellular assays (CAA) with the SH-S5SY cell line performed on these library members revealed that the couplings did not affect the antioxidant activity elicited by CR-6 itself. More interestingly, results from the intraperitoneal administration of selected library components in rats showed that compounds 2b, 2c and 2d were able to pass across the BBB. In particular, the amino acid compound 2d was the most penetrating derivative (15.8 ± 1.7 nmol/g brain with respect to the 4.0 ± 1.2 nmol/g brain found for the parent CR-6).
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vázquez-Jiménez
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Garrido
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain.
authors.forename: Martina
authors.initials: M
authors.lastname: Miceli
authors.affiliation: Centre d'Investigació i Desenvolupament de Barcelona (CID-CSIC), 08028 Barcelona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Prats
authors.affiliation: Institute of Cellular and Molecular Biology, University Miguel Hernández, 03202 Elche, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ferrer-Montiel
authors.affiliation: Institute of Research in Biomedicine, 08028 Barcelona, Spain.
authors.forename: Meritxell
authors.initials: M
authors.lastname: Teixidó
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain.
authors.forename: Ciril
authors.initials: C
authors.lastname: Jimeno
authors.affiliation: Department of Biological Chemistry and Molecular Modeling, Institute of Advanced Chemistry of Catalonia (IQAC-CSIC), 08034 Barcelona, Spain. Electronic address: angel.messeguer@iqac.csic.es.
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D008297:Male; D010539:Permeability; D051381:Rats; D017207:Rats, Sprague-Dawley; D026361:Reactive Nitrogen Species / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species
keywords: Antioxidants; Blood-brain barrier permeability; CR-6; Neuroprotective agents; Oxidative stress