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

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

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DE 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. 291, pp. 253-263. ISSN 0009-2797. eISSN 1872-7786. Available under: doi: 10.1016/j.cbi.2018.06.029

@article{deSouzaFagundes2018-06-23Corre-42815, title={Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties}, year={2018}, doi={10.1016/j.cbi.2018.06.029}, 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} }

Marques, Lucas Bonfim 2018-06-23 Prazeres, Pedro H.D.M. Szamosvàri, Dàvid Szamosvàri, Dàvid da Silva, Adilson David 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. Marques, Lucas Bonfim 2018-07-07T14:40:02Z de Souza-Fagundes, Elaine Maria Delp, Johannes Leist, Marcel Correlation of structural features of novel 1,2,3-triazoles with their neurotoxic and tumoricidal properties eng Prazeres, Pedro H.D.M. da Silva, Adilson David Delp, Johannes Kisitu, Jaffar 2018-07-07T14:40:02Z Carmo, Arturene Maria Lino Leist, Marcel Carmo, Arturene Maria Lino Böttcher, Thomas de Souza-Fagundes, Elaine Maria Böttcher, Thomas Kisitu, Jaffar

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