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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Discovery and synthesis of sulfur-containing 6-substituted 5,8-dimethoxy-1,4-naphthoquinone oxime derivatives as new and potential anti-MDR cancer agents
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Discovery and synthesis of sulfur-containing 6-substituted 5,8-dimethoxy-1,4-naphthoquinone oxime derivatives as new and potential anti-MDR cancer agents

机译：含硫的6-取代的5,8-二甲氧基-1,4-萘醌肟衍生物的发现和合成作为新的和潜在的抗MDR癌症剂

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Multi-drug resistance (MDR) to anticancer drugs is the primary impediment to successful treatment of cancer. Hunting for new compounds with potent anti-MDR activity is an effectual approach to conquer cancer drug resistance. In this work, 33 new sulfur-containing 1,4-naphthoquinone oxime derivatives were prepared and investigated for their cytotoxicity against a panel of tumor cell lines and fibroblast normal cell line. Cell-based assay showed that most of target compounds displayed more potent cytotoxic potency than positive controls. Meanwhile, all of compounds were non-toxic to normal cells. More importantly, the cytotoxic activity of these oxime derivatives toward drug-resistant cancer cell lines was found to be much stronger than that toward drug-susceptible cell lines (anti-drug resistance coefficient (ADRC) 1). Of these, compound 12 m was identified as the most effective molecule with IC50 values in the range of 0.29 +/- 0.01 to 1.33 +/- 0.05 mu M toward MDR sublines. Further mechanism studies demonstrated that 12 m could inhibit colony formation, cause G1 phase arrest and promote cell apoptosis mediated by augmenting Bax/Bcl-2 ratio of Be17402/5-FU cells. Our findings provide promising start points for development of sulfur-containing 1,4-naphthoquinone oxime derivatives as potential anti MDR agents. (C) 2019 Elsevier Masson SAS. All rights reserved.
机译：对抗癌药物的多药抗性（MDR）是成功治疗癌症的主要障碍。捕捉具有有效抗MDR活性的新化合物是征服癌症耐药性的有效方法。在这项工作中，制备了33种含硫的1,4-萘醌肟衍生物，并针对肿瘤细胞系和成纤维细胞正常细胞系的细胞毒性研究。基于细胞的测定表明，大多数靶化合物显示出比阳性对照更有效的细胞毒性效力。同时，所有化合物对正常细胞无毒。更重要的是，朝向耐药癌细胞系这些肟衍生物的细胞毒性活性被认为是比朝向药物敏感细胞系（抗耐药性系数（ADRC）→1）强得多。其中，化合物12M被鉴定为具有0.29 +/- 0.01至1.33 +/-0.05μm的IC 50值的最有效分子朝向MDR载列。进一步的机制研究表明，12米可以抑制菌落形成，导致G1相阻滞和促进通过增强Bax / Bcl-2比的Be17402 / 5-Fu细胞介导的细胞凋亡。我们的研究结果提供了含硫1,4-萘醌肟衍生物作为潜在的抗MDR试剂的开发点。 （c）2019年Elsevier Masson SAS。版权所有。

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