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Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties.
de Souza-Fagundes, Elaine Maria; Delp, Johannes; Prazeres, PedroH D M; Marques, Lucas Bonfim; Carmo, Arturene Maria Lino; Stroppa, Pedro Henrique Fazza; Glanzmann, Nicolas; Kisitu, Jaffar; Szamosvàri, Dàvid; Böttcher, Thomas; Leist, Marcel; da Silva, Adilson David.
Afiliación
  • de Souza-Fagundes EM; Chair for In Vitro Toxicology and Biomedicine, Inaugurated By the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany; Physiology and Biophysics Department, Federal University of Minas Gerais, Belo Horizonte, Brazil. Electronic address: elainefagundes@ufmg.br.
  • Delp J; Chair for In Vitro Toxicology and Biomedicine, Inaugurated By the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany; Cooperative Doctorate College InViTe, Germany.
  • Prazeres PDM; Physiology and Biophysics Department, Federal University of Minas Gerais, Belo Horizonte, Brazil.
  • Marques LB; Physiology and Biophysics Department, Federal University of Minas Gerais, Belo Horizonte, Brazil.
  • Carmo AML; Department of Chemistry, I.C.E, Federal University of Juiz de Fora, Juiz de Fora, Brazil.
  • Stroppa PHF; Department of Chemistry, I.C.E, Federal University of Juiz de Fora, Juiz de Fora, Brazil.
  • Glanzmann N; Department of Chemistry, I.C.E, Federal University of Juiz de Fora, Juiz de Fora, Brazil.
  • Kisitu J; Chair for In Vitro Toxicology and Biomedicine, Inaugurated By the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany; Graduate School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany.
  • Szamosvàri D; Graduate School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany; Department of Chemistry, University of Konstanz, Konstanz, Germany.
  • Böttcher T; Graduate School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany; Department of Chemistry, University of Konstanz, Konstanz, Germany.
  • Leist M; Chair for In Vitro Toxicology and Biomedicine, Inaugurated By the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany; Graduate School Chemical Biology (KoRS-CB), University of Konstanz, Konstanz, Germany.
  • da Silva AD; Department of Chemistry, I.C.E, Federal University of Juiz de Fora, Juiz de Fora, Brazil.
Chem Biol Interact ; 291: 253-263, 2018 Aug 01.
Article en En | MEDLINE | ID: mdl-29944877
Triazoles are interesting templates for novel chemotherapeutic drugs. We synthesized here 17 1,3,4-substituted-1,2,3-triazoles that differed in their 1'-substituent (variable alkyl chain lengths C3-C12), the 3'-substituent (no substituent, -methyl or -propyl) or the salt form obtained. Several of the compounds were cytotoxic (µM range) for tumor cells (HL-60, Jurkat, MCF-7, HCT-116), and when the effect was compared to non-transformed cells (Vero), selectivity ratios of up to 23-fold were obtained. To estimate the liability of these potential drug candidates for triggering neurotoxicity, we used the LUHMES cell-based NeuriTox assay. This test quantifies damage to the neurites of human neurons. The four most potent tumoricidal compounds were found to be neurotoxic in a concentration range similar to the one showing tumor cell toxicity. As the neurites of the LUHMES neurons were affected at >4-fold lower concentrations than the overall cell viability, the novel triazoles were classified as specific neurotoxicants. The structure-activity relationship (SAR) for neurotoxicity was sharply defined and correlated with the one for anti-neoplastic activity. Based on this SAR, two non-neurotoxic compounds were predicted, and testing in the NeuriTox assay confirmed this prediction. In summary, the panel of novel triazoles generated and characterized here, allowed to define structural features associated with cytotoxicity and neurotoxicity. Moreover, the study shows that potential neurotoxic side effects may be predicted early in drug development if highly sensitive test methods for neurite integrity are applied.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Neoplasias / Neurotoxinas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Chem Biol Interact Año: 2018 Tipo del documento: Article Pais de publicación: Irlanda

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triazoles / Neoplasias / Neurotoxinas Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Chem Biol Interact Año: 2018 Tipo del documento: Article Pais de publicación: Irlanda