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.
Chair for In Vitro Toxicology and Biomedicine, Inaugurated By the Doerenkamp-Zbinden Foundation, University of Konstanz, Konstanz, Germany; Cooperative Doctorate College InViTe, Germany.
Chem Biol Interact. 2018 Aug 1;291:253-263. doi: 10.1016/j.cbi.2018.06.029. Epub 2018 Jun 23.
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.
三氮唑是新型化疗药物的有趣模板。我们在这里合成了 17 种 1'取代基（不同长度的 C3-C12 烷基链）、3'取代基（无取代基、-甲基或 -丙基）或获得的盐形式不同的 1,3,4-取代-1,2,3-三唑。其中几种化合物对肿瘤细胞（HL-60、Jurkat、MCF-7、HCT-116）具有细胞毒性（μM 范围），当与未转化细胞（Vero）进行比较时，获得了高达 23 倍的选择性比。为了估计这些潜在药物候选物引发神经毒性的可能性，我们使用了基于 LUHMES 细胞的 NeuriTox 测定法。该测试定量测量人类神经元的神经突损伤。发现四种最有效的杀肿瘤化合物在与引起肿瘤细胞毒性相似的浓度范围内具有神经毒性。由于 LUHMES 神经元的神经突受到的影响比整体细胞活力低 4 倍以上，因此新型三唑类化合物被归类为特异性神经毒素。神经毒性的结构-活性关系（SAR）定义明确，并与抗肿瘤活性的 SAR 相关。基于该 SAR，预测了两种非神经毒性化合物，并在 NeuriTox 测定中证实了这一预测。总之，这里生成和表征的新型三唑类化合物的研究结果，定义了与细胞毒性和神经毒性相关的结构特征。此外，该研究表明，如果应用神经突完整性的高度敏感测试方法，可能会在药物开发早期预测潜在的神经毒性副作用。
