title: Synthesis and biological evaluation of novel 5-hydroxylaminoisoxazole derivatives as lipoxygenase inhibitors and metabolism enhancing agents.
abstract: A versatile synthesis of novel 5-hydroxylaminoisoxazoles bearing adamantane moieties has been accomplished using the heterocyclization reactions of readily available unsaturated esters by the treatment with tetranitromethane in the presence of triethylamine and subsequent reduction of resulting 5-nitroisoxazoles by SnCl2 with the participation of THF. A number of obtained isoxazole derivatives were evaluated for their antioxidative activity, inhibition of lipoxygenases and impact on the rat liver mitochondria. The majority of tested compounds demonstrated moderate antiradical activity in DPPH test (up to EC50 16μM). The same compounds strongly inhibited soybean lipoxygenase (up to IC50 0.4μM) and Fe(2+)- and Fe(3+)-induced lipid peroxidation (LP) of rat brain cortex homogenate (up to IC50 0.3μM). All tested isoxazole derivatives promoted the phosphorylating respiratory activity simultaneously with maximal stimulated respiratory activity of mitochondria and do not reveal any toxicity towards the primary culture of rat cortex neurons.
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia; IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia. Electronic address: elaver@org.chem.msu.ru.
authors.forename: Elena B
authors.initials: EB
authors.lastname: Averina
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Vasilenko
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia.
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Gracheva
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia.
authors.forename: Yuri K
authors.initials: YK
authors.lastname: Grishin
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia; IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Eugene V
authors.initials: EV
authors.lastname: Radchenko
authors.affiliation: Volgograd State Technical University, VSTU, Lenina Avenue, 28, Volgograd 400005, Russia.
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Burmistrov
authors.affiliation: Volgograd State Technical University, VSTU, Lenina Avenue, 28, Volgograd 400005, Russia.
authors.forename: Gennady M
authors.initials: GM
authors.lastname: Butov
authors.affiliation: IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Margarita E
authors.initials: ME
authors.lastname: Neganova
authors.affiliation: IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Tatyana P
authors.initials: TP
authors.lastname: Serkova
authors.affiliation: IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Olga M
authors.initials: OM
authors.lastname: Redkozubova
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia; IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Elena F
authors.initials: EF
authors.lastname: Shevtsova
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia; IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia. Electronic address: milaeva@med.chem.msu.ru.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Milaeva
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia.
authors.forename: Tamara S
authors.initials: TS
authors.lastname: Kuznetsova
authors.affiliation: Lomonosov Moscow State University, Department of Chemistry, Leninskie Gory, 1-3, Moscow 119991, Russia; IPAC RAS, Severnyi Proezd, 1, Chernogolovka, Moscow Region, 142432, Russia.
authors.forename: Nikolay S
authors.initials: NS
authors.lastname: Zefirov
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000037:antagonists & inhibitors; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D045744:Cell Line, Tumor; D016166:Free Radical Scavengers / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008084:Lipoxygenase / Q000378:metabolism*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D009840:Oligomycins / Q000494:pharmacology; D010851:Picrates / Q000037:antagonists & inhibitors; D061251:Primary Cell Culture; D051381:Rats; D013025:Glycine max / Q000737:chemistry / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D016166:Free Radical Scavengers; D007555:Isoxazoles; D016859:Lipoxygenase Inhibitors; D009840:Oligomycins; D010851:Picrates; D000968:Antimycin A; C004931:1,1-diphenyl-2-picrylhydrazyl; D008084:Lipoxygenase
keywords: Heterocyclization; Isoxazole; Lipoxygenase; Mitochondria; Reduction