title: Spin trapping and cytoprotective properties of fluorinated amphiphilic carrier conjugates of cyclic versus linear nitrones.
abstract: Nitrones have been employed as spin trapping reagent as well as pharmacological agent against neurodegenerative diseases and ischemia-reperfusion induced injury. The structure-activity relationship was explored for the two types of nitrones, i.e., cyclic (DMPO) and linear (PBN), which are conjugated to a fluorinated amphiphilic carrier (FAC) for their cytoprotective properties against hydrogen peroxide (H(2)O(2)), 3-morpholinosynonimine hydrochloride (SIN-1), and 4-hydroxynonenal (HNE) induced cell death on bovine aortic endothelial cells. The compound FAMPO was synthesized and characterized, and its physical-chemical and spin trapping properties were explored. Cytotoxicity and cytoprotective properties of various nitrones either conjugated and nonconjugated to FAC (i.e., AMPO, FAMPO, PBN, and FAPBN) were assessed using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium (MTT) reduction assay. Results show that of all the nitrones tested, FAPBN is the most protective against H(2)O(2), but FAMPO and to a lesser extent its unconjugated form, AMPO, are more protective against SIN-1 induced cytotoxicity. However, none of the nitrones used protect the cells from HNE-induced cell death. The difference in the cytoprotective properties observed between the cyclic and linear nitrones may arise from the differences in their intrinsic antioxidant properties and localization in the cell.
authors.affiliation: Laboratoire de Chimie BioOrganique et des Systèmes Moléculaires Vectoriels, Faculté des Sciences, Université d'Avignon et des Pays de Vaucluse, 33 Rue Louis Pasteur, 84000 Avignon, France. gregory.durand@univ-avignon.fr
authors.forename: Grégory
authors.initials: G
authors.lastname: Durand
authors.forename: Robert A
authors.initials: RA
authors.lastname: Prosak
authors.forename: Yongbin
authors.initials: Y
authors.lastname: Han
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Ortial
authors.forename: Antal
authors.initials: A
authors.lastname: Rockenbauer
authors.forename: Bernard
authors.initials: B
authors.lastname: Pucci
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Villamena
mesh_terms: D000447:Aldehydes / Q000633:toxicity; D000818:Animals; D000959:Antihypertensive Agents / Q000633:toxicity; D002417:Cattle; D003432:Cross-Linking Reagents / Q000633:toxicity; D004337:Drug Carriers / Q000737:chemistry*; D042783:Endothelial Cells / Q000187:drug effects; D005461:Fluorine / Q000737:chemistry*; D006861:Hydrogen Peroxide / Q000633:toxicity; D008981:Molsidomine / Q000031:analogs & derivatives / Q000633:toxicity; D009589:Nitrogen Oxides / Q000737:chemistry* / Q000633:toxicity; D019097:Spin Trapping
chemical_list: D000447:Aldehydes; D000959:Antihypertensive Agents; D003432:Cross-Linking Reagents; D004337:Drug Carriers; D009589:Nitrogen Oxides; C015388:nitrones; D005461:Fluorine; C002385:linsidomine; D006861:Hydrogen Peroxide; D008981:Molsidomine; C027576:4-hydroxy-2-nonenal
references.citation: J Med Chem. 1987 Jun;30(6):1097-100
references.pmid: 3585907
references.citation: Biochimie. 1998 May-Jun;80(5-6):515-30
references.pmid: 9782390
references.citation: J Med Chem. 1995 Jan 20;38(2):258-65
references.pmid: 7830268
references.citation: J Phys Chem A. 2007 Jan 18;111(2):384-91
references.pmid: 17214476
references.citation: CNS Drugs. 2004;18(15):1071-84
references.pmid: 15581379
references.citation: Free Radic Biol Med. 2008 Nov 15;45(10):1361-74
references.pmid: 18793715
references.citation: Cardiovasc Drugs Ther. 2006 Apr;20(2):147-9
references.pmid: 16534547
references.citation: Nat Rev Drug Discov. 2007 Aug;6(8):662-80
references.pmid: 17667957
references.citation: J Org Chem. 1999 May 14;64(10):3554-3556
references.pmid: 11674480
references.citation: Arterioscler Thromb Vasc Biol. 2007 Nov;27(11):2340-7
references.pmid: 17872449
references.citation: Chem Biodivers. 2007 Sep;4(9):2253-67
references.pmid: 17886845
references.citation: J Biochem Biophys Methods. 1996 Jul 10;32(3):183-90
references.pmid: 8844325
references.citation: Nature. 2000 Apr 13;404(6779):787-90
references.pmid: 10783895
references.citation: J Neurochem. 2001 Oct;79(2):445-55
references.pmid: 11677273
references.citation: Cardiovasc Res. 2006 May 1;70(2):181-90
references.pmid: 16580655
references.citation: Bioorg Med Chem Lett. 2006 Mar 1;16(5):1111-4
references.pmid: 16386903
references.citation: J Am Chem Soc. 2003 Jul 9;125(27):8364-70
references.pmid: 12837108
references.citation: Chem Res Toxicol. 2004 Feb;17(2):250-7
references.pmid: 14967013
references.citation: Proc Natl Acad Sci U S A. 1990 Feb;87(4):1620-4
references.pmid: 2154753
references.citation: J Biol Chem. 2007 Jan 12;282(2):1183-92
references.pmid: 17105724
references.citation: Free Radic Res. 1995 Jul;23(1):1-14
references.pmid: 7647915
references.citation: J Am Chem Soc. 2002 Jul 24;124(29):8719-24
references.pmid: 12121116
references.citation: J Med Chem. 2006 May 4;49(9):2812-20
references.pmid: 16640342
references.citation: Eur J Cancer. 1996 Jan;32A(1):30-8
references.pmid: 8695238
references.citation: J Cardiovasc Pharmacol. 1999 Feb;33(2):295-300
references.pmid: 10028940
references.citation: Prog Lipid Res. 2003 Jul;42(4):318-43
references.pmid: 12689622
references.citation: Ann N Y Acad Sci. 2000;899:222-37
references.pmid: 10863542
references.citation: Chem Rev. 1998 Jul 30;98(5):1755-1786
references.pmid: 11848948
references.citation: Arch Biochem Biophys. 1993 Feb 1;300(2):535-43
references.pmid: 8434935
references.citation: Expert Opin Investig Drugs. 2002 Oct;11(10):1407-35
references.pmid: 12387703
references.citation: J Pharmacol Exp Ther. 2009 May;329(2):515-23
references.pmid: 19201989
references.citation: Bioorg Med Chem Lett. 2003 Mar 10;13(5):859-62
references.pmid: 12617908
references.citation: Int J Pharm. 2009 Sep 11;379(2):301-8
references.pmid: 19501144
references.citation: J Neurochem. 2005 Nov;95(4):962-73
references.pmid: 16135084
references.citation: J Neurochem. 1997 Mar;68(3):1173-82
references.pmid: 9048764
references.citation: Biochem J. 1993 Dec 1;296 ( Pt 2):341-5
references.pmid: 8257422
references.citation: Proc Natl Acad Sci U S A. 1980 Feb;77(2):1159-63
references.pmid: 6928666
references.citation: Neurochem Int. 2008 Mar-Apr;52(4-5):776-85
references.pmid: 17977619
references.citation: J Med Chem. 2007 Aug 23;50(17):3976-9
references.pmid: 17649989
references.citation: J Phys Chem A. 2007 Oct 4;111(39):9995-10001
references.pmid: 17845014
references.citation: Mol Cell Biol. 2000 Oct;20(19):7311-8
references.pmid: 10982848
references.citation: J Neurochem. 1997 Sep;69(3):1252-8
references.pmid: 9282950
references.citation: Free Radic Biol Med. 1998 Mar 1;24(4):522-8
references.pmid: 9559863
references.citation: J Phys Chem A. 2005 Mar 3;109(8):1662-74
references.pmid: 16833491
references.citation: Mech Ageing Dev. 2002 Apr 30;123(8):1021-31
references.pmid: 12044951
references.citation: Antioxid Redox Signal. 2004 Jun;6(3):619-29
references.pmid: 15130289
references.citation: J Am Chem Soc. 2007 Jul 4;129(26):8177-91
references.pmid: 17564447
references.citation: Circ Res. 2006 Oct 27;99(9):924-32
references.pmid: 17068300
references.citation: Arch Biochem Biophys. 1996 Sep 15;333(2):419-26
references.pmid: 8809082
references.citation: J Phys Chem A. 2008 Mar 20;112(11):2447-55
references.pmid: 18303874
references.citation: Free Radic Biol Med. 1990;8(4):363-72
references.pmid: 2165975
references.citation: J Med Chem. 2003 Nov 20;46(24):5230-7
references.pmid: 14613325
references.citation: Antioxid Redox Signal. 2007 Jan;9(1):49-89
references.pmid: 17115887
references.citation: Cell Struct Funct. 2008;33(1):51-9
references.pmid: 18360009
references.citation: Org Biomol Chem. 2005 Sep 7;3(17):3220-7
references.pmid: 16106305
references.citation: J Phys Chem A. 2008 Dec 4;112(48):12498-509
references.pmid: 18998656
references.citation: J Biol Chem. 2005 Apr 29;280(17):17149-53
references.pmid: 15749715
references.citation: Free Radic Biol Med. 2000 Jun 15;28(12):1806-14
references.pmid: 10946222
references.citation: Org Biomol Chem. 2004 Mar 21;2(6):927-34
references.pmid: 15007424
references.citation: J Org Chem. 2008 Nov 7;73(21):8142-53
references.pmid: 18823145
references.citation: Neurochem Res. 1998 Nov;23(11):1403-10
references.pmid: 9814551
references.citation: Chemistry. 2007;13(33):9344-54
references.pmid: 17729216
references.citation: Chem Rev. 2005 Aug;105(8):2999-3093
references.pmid: 16092826
references.citation: Arch Biochem Biophys. 2005 Jul 1;439(1):80-90
references.pmid: 15946642
references.citation: Adv Drug Deliv Rev. 2000 Mar 15;41(1):55-74
references.pmid: 10699305
references.citation: Atherosclerosis. 2006 Jul;187(1):1-17
references.pmid: 16313912