Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties

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2018
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de Souza-Fagundes, Elaine Maria
Prazeres, Pedro H.D.M.
Marques, Lucas Bonfim
Carmo, Arturene Maria Lino
Szamosvàri, Dàvid
da Silva, Adilson David
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Chemico-biological interactions. 2018, 291, pp. 253-263. ISSN 0009-2797. eISSN 1872-7786. Available under: doi: 10.1016/j.cbi.2018.06.029
Zusammenfassung

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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Fachgebiet (DDC)
570 Biowissenschaften, Biologie
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1,2,3-triazoles Cytotoxicity Neurotoxicity Structure-activity relationship
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ISO 690DE SOUZA-FAGUNDES, Elaine Maria, Johannes DELP, Pedro H.D.M. PRAZERES, Lucas Bonfim MARQUES, Arturene Maria Lino CARMO, Jaffar KISITU, Dàvid SZAMOSVÀRI, Thomas BÖTTCHER, Marcel LEIST, Adilson David DA SILVA, 2018. Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties. In: Chemico-biological interactions. 2018, 291, pp. 253-263. ISSN 0009-2797. eISSN 1872-7786. Available under: doi: 10.1016/j.cbi.2018.06.029
BibTex
@article{deSouzaFagundes2018-06-23Corre-42815,
  year={2018},
  doi={10.1016/j.cbi.2018.06.029},
  title={Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties},
  volume={291},
  issn={0009-2797},
  journal={Chemico-biological interactions},
  pages={253--263},
  author={de Souza-Fagundes, Elaine Maria and Delp, Johannes and Prazeres, Pedro H.D.M. and Marques, Lucas Bonfim and Carmo, Arturene Maria Lino and Kisitu, Jaffar and Szamosvàri, Dàvid and Böttcher, Thomas and Leist, Marcel and da Silva, Adilson David}
}
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