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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DOI：
10.1016/j.cbi.2018.06.029
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发表时间：
2018-08-01
影响因子：
5.1
通讯作者：
da Silva, Adilson David
中科院分区：
文献类型：
--
作者：
de Souza-Fagundes, Elaine Maria;Delp, Johannes;da Silva, Adilson David
三唑类药物是新型化疗药物的有趣模板。我们在这里合成了17个1,3,4-取代-1,2,3-三唑，它们的1 ‘取代基（可变烷基链长C3-C12）、3’取代基（无取代基、-甲基或-丙基）或盐形式不同。其中一些化合物对肿瘤细胞（HL-60, Jurkat, MCF-7, HCT-116）具有细胞毒性（μ M范围），当与非转化细胞（Vero）进行比较时，选择性比高达23倍。为了估计这些潜在的候选药物对触发神经毒性的责任，我们使用了LUHMES细胞为基础的NeuriTox测定。这个测试量化了对人类神经元神经突的损伤。四种最有效的杀肿瘤化合物被发现具有神经毒性，其浓度范围与显示肿瘤细胞毒性的浓度范围相似。由于LUHMES神经元的神经突受到的影响浓度低于整体细胞活力的4倍，因此新型三唑被归类为特异性神经毒物。神经毒性的构效关系（SAR）被明确定义，并与抗肿瘤活性的构效关系相关。基于该SAR，预测了两种非神经毒性化合物，并且在NeuriTox试验中的测试证实了这一预测。总之，在这里生成和表征的新型三唑组，允许定义与细胞毒性和神经毒性相关的结构特征。此外，该研究表明，如果采用高度敏感的神经突完整性测试方法，可能会在药物开发的早期预测潜在的神经毒性副作用。
Triazoles are interesting templates for novel chemotherapeutic drugs. We synthesized here 17 1,3,4-substituted-1,2,3-triazoles that differed in their l'-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 (mu M 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.