Synthesis of improved lysomotropic autophagy inhibitors.
Synthesis of improved lysomotropic autophagy inhibitors.
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DOI：
10.1021/jm501586m
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发表时间：
2015-03
影响因子：
7.3
通讯作者：
Tong Wang;Megan L. Goodall;P. Gonzales;Mario Sepúlveda;Katie R. Martin;S. Gately;J. MacKeigan
中科院分区：
文献类型：
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作者：
Tong Wang;Megan L. Goodall;P. Gonzales;Mario Sepúlveda;Katie R. Martin;S. Gately;J. MacKeigan
自噬是一种保守的细胞途径，用于在基本和应激（如营养剥夺，化疗治疗）下通过溶酶体分解回收营养物质。已知癌基因诱导自噬，这可能被癌症利用来维持细胞存活。为了确定对癌症具有潜在治疗价值的自噬抑制剂，我们筛选了一组抗疟疾药物，发现奎宁（QN）的自噬抑制效力比氯喹（CQ）高60倍，氯喹是一种众所周知的自噬抑制剂，通过破坏溶酶体活性起作用。尽管具有理想的自噬抑制特性，但QN显示出相当大的细胞毒性。因此，我们设计并合成了一系列新的QN类似物，并研究了它们对自噬抑制和细胞活力的影响。值得注意的是，我们发现含有1,2,3,4-四氢吖啶骨架的两种化合物（33和34）具有有限的细胞毒性，但具有很强的自噬抑制特性。总之，这些改进的溶性粒细胞自噬抑制剂可以作为抗癌药物与常规疗法联合使用。
Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of antimalarial agents and found that quinacrine (QN) had 60-fold higher potency of autophagy inhibition than chloroquine (CQ), a well-known autophagy inhibitor that functions by disrupting lysosomal activity. Despite desirable autophagy inhibiting properties, QN showed considerable cytotoxicity. Therefore, we designed and synthesized a novel series of QN analogs and investigated their effects on autophagy inhibition and cell viability. Notably, we found two compounds (33 and 34), bearing a backbone of 1,2,3,4-tetrahydroacridine, had limited cytotoxicity yet strong autophagy inhibition properties. In conclusion, these improved lysomotropic autophagy inhibitors may have use as anticancer agents in combination with conventional therapies.