title: [Fe(CN)5(isoniazid)](3-): an iron isoniazid complex with redox behavior implicated in tuberculosis therapy.
abstract: Tuberculosis has re-emerged as a worldwide threat, which has motivated the development of new drugs. The antituberculosis complex Na3[Fe(CN)5(isoniazid)] (IQG607) in particular is of interest on account of its ability to overcome resistance. IQG607 has the potential for redox-mediated-activation, in which an acylpyridine (isonicotinoyl) radical could be generated without assistance from the mycobacterial KatG enzyme. Here, we have investigated the reactivity of IQG607 toward hydrogen peroxide and superoxide, well-known intracellular oxidizing agents that could play a key role in the redox-mediated-activation of this compound. HPLC, NMR and electronic spectroscopy studies showed a very fast oxidation rate for bound isoniazid, over 460-fold faster than free isoniazid oxidation. A series of EPR spin traps were used for detection of isonicotinoyl and derived radicals bound to iron. This is the first report for an isonicotinoyl radical bound to a metal complex, supported by (14)N and (1)H hyperfine splittings for the POBN and PBN trapped radicals. POBN and PBN exhibited average hyperfine coupling constants of aN=15.6, aH=2.8 and aN=15.4, aH=4.7, respectively, which are in close agreement to the isonicotinoyl radical. Radical generation is thought to play a major role in the mechanism of action of isoniazid and this work provides strong evidence for its production within IQG607, which, along with biological and chemical oxidation data, support a redox-mediated activation mechanism. More generally the concept of redox activation of metallo prodrugs could be applied more widely for the design of therapeutic agents with novel mechanisms of action.
authors.affiliation: Laboratório de Bioinorgânica, Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Cx. Postal 6021, Fortaleza 60440-900, Brazil; Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom. Electronic address: eduardohss@dqoi.ufc.br.
authors.forename: Eduardo Henrique Silva
authors.initials: EH
authors.lastname: Sousa
authors.affiliation: Laboratório de Bioinorgânica, Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Cx. Postal 6021, Fortaleza 60440-900, Brazil.
authors.forename: Francisca Gilmara
authors.initials: FG
authors.lastname: de Mesquita Vieira
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Butler
authors.affiliation: Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil; Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio ande do Sul, Av. Ipiranga, 6681, Tecnopuc, Prédio 92A Partenon, Porto Alegre 90619-900, RS, Brazil.
authors.forename: Luiz Augusto
authors.initials: LA
authors.lastname: Basso
authors.affiliation: Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil; Centro de Pesquisas em Biologia Molecular e Funcional, Pontifícia Universidade Católica do Rio ande do Sul, Av. Ipiranga, 6681, Tecnopuc, Prédio 92A Partenon, Porto Alegre 90619-900, RS, Brazil.
authors.forename: Diógenes S
authors.initials: DS
authors.lastname: Santiago
authors.affiliation: Laboratório de Bioinorgânica, Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Cx. Postal 6021, Fortaleza 60440-900, Brazil.
authors.forename: Izaura C N
authors.initials: IC
authors.lastname: Diógenes
authors.affiliation: Laboratório de Bioinorgânica, Departamento de Química Orgânica e Inorgânica, Universidade Federal do Ceará, Cx. Postal 6021, Fortaleza 60440-900, Brazil; Instituto Nacional de Ciência e Tecnologia em Tuberculose, Pontifícia Universidade Católica do Rio Grande do Sul, Porto Alegre, Brazil.
authors.forename: Luiz Gonzaga de França
authors.initials: LG
authors.lastname: Lopes
authors.affiliation: Department of Chemistry, University of Warwick, Coventry CV4 7AL, United Kingdom. Electronic address: p.j.sadler@warwick.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000627:therapeutic use*; D004578:Electron Spin Resonance Spectroscopy; D005296:Ferrous Compounds / Q000737:chemistry / Q000627:therapeutic use*; D006801:Humans; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D010084:Oxidation-Reduction; D013481:Superoxides / Q000737:chemistry; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D005296:Ferrous Compounds; C576457:pentacyano(isoniazid)ferrate(II); D013481:Superoxides; D007538:Isoniazid
keywords: EPR radical trapping; Isoniazid; Metallodrugs; Pentacyanoferrate; Tuberculosis