title: Synthesis of neamine-based pseudodisaccharides as potential vestibulotoxic agents to treat vertigo in Ménière's disease.
abstract: Ménière's disease (MD) is a progressive disease of the inner ear characterized by recurring attacks of disabling vertigo, hearing loss and tinnitus. Patients who do not respond to vestibular sedatives or steroids may require an intratympanic application of aminoglycoside antibiotics, which destroys the vestibular function of the affected ear in order to avoid the debilitating vertigo attacks. Although effective, this procedure causes hearing loss in almost one third of the patients due to the aminoglycosides cochlear toxicity. Here we describe the synthesis of two pseudodisaccharides structurally related to neamime aiming to mimic the aminoglycosides pharmacophore core by replacing their toxic amine by azide and hydroxyl groups. Products 1 and 2 selectively promoted 'in vivo' damage to vestibular tissues without causing hearing loss or cochlear toxicity. Therefore, these pseudodisaccharides stand as promising lead compounds for the development of a safer and more effective therapeutic procedure to manage the symptoms of MD severe dizziness.
authors.affiliation: Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto-SP, Brazil.
authors.forename: Flávio Roberto
authors.initials: FR
authors.lastname: Pinsetta
authors.forename: Daniel Fábio
authors.initials: DF
authors.lastname: Kawano
authors.forename: Marcelo Rodrigues
authors.initials: MR
authors.lastname: de Carvalho
authors.forename: José Antônio A
authors.initials: JA
authors.lastname: de Oliveira
authors.forename: Alexandre P
authors.initials: AP
authors.lastname: Corrado
authors.forename: Miguel Ângelo
authors.initials: MÂ
authors.lastname: Hyppolito
authors.forename: Ivone
authors.initials: I
authors.lastname: Carvalho
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry; D000818:Animals; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D003051:Cochlea / Q000166:cytology / Q000187:drug effects; D004187:Disaccharides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005601:Framycetin / Q000737:chemistry*; D006168:Guinea Pigs; D006198:Hair Cells, Auditory / Q000187:drug effects; D006801:Humans; D008575:Meniere Disease / Q000188:drug therapy; D008855:Microscopy, Electron, Scanning; D018716:Molecular Mimicry; D015394:Molecular Structure; D014717:Vertigo / Q000188:drug therapy*
chemical_list: C585417:4-O-(galactopyranosyl)-1,3-diazido-1,2,3-trideoxy-myo-inositol; D000617:Aminoglycosides; D001386:Azides; D004187:Disaccharides; D005601:Framycetin; C488396:neamine