title: Substituted pyrazolones require N2 hydrogen bond donating ability to protect against cytotoxicity from protein aggregation of mutant superoxide dismutase 1.
abstract: Amyotrophic lateral sclerosis (ALS) is a debilitating and fatal neurodegenerative disease. Although the cause remains unknown, misfolded protein aggregates are seen in neurons of sporadic ALS patients, and familial ALS mutations, including mutations in superoxide dismutase 1 (SOD1), produce proteins with an increased propensity to misfold and aggregate. A structure activity relationship of a lead scaffold exhibiting neuroprotective activity in a G93A-SOD1 mouse model for ALS has been further investigated in a model PC12 cellular assay. Synthesis of biotinylated probes at the N(1) nitrogen of the pyrazolone ring gave compounds (5d-e) that retained activity within 10-fold of the proton-bearing lead compound (5a) and were equipotent with a sterically less cumbersome N(1)-methyl substituted analogue (5b). However, when methyl substitution was introduced at N(1) and N(2) of the pyrazolone ring, the compound was inactive (5c). These data led us to investigate further the pharmacophoric nature of the pyrazolone unit. A range of N(1) substitutions were tolerated, leading to the identification of an N(1)-benzyl substituted pyrazolone (5m), equipotent with 5a. Substitution at N(2) or excision of N(2), however, removed all activity. Therefore, the hydrogen bond donating ability of the N(2)-H of the pyrazolone ring appears to be a critical part of the structure, which will influence further analogue synthesis.
authors.affiliation: Department of Chemistry, Northwestern University, Evanston, IL, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Trippier
authors.forename: Radhia
authors.initials: R
authors.lastname: Benmohamed
authors.forename: Radhia
authors.initials: R
authors.lastname: Benmohammed
authors.forename: Donald R
authors.initials: DR
authors.lastname: Kirsch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Silverman
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D009154:Mutation; D016716:PC12 Cells; D017510:Protein Folding; D047069:Pyrazolones / Q000737:chemistry* / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism / Q000633:toxicity; D000072105:Superoxide Dismutase-1
chemical_list: D003517:Cyclopentanes; D047069:Pyrazolones; C000606290:SOD1 protein, human; C007201:cyclopentanone; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1