Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias.
Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias.
复制标题
异喹啉缩氨基硫脲显示出有效的抗癌活性，并具有体内对抗侵袭性白血病的功效。
DOI：
10.1039/c9md00594c
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发表时间：
2020
影响因子：
4.1
通讯作者：
Stuparu,An
中科院分区：
文献类型：
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作者：
Sun,DanielL;Poddar,Soumya;Pan,RoyD;Rosser,EthanW;Abt,EvanR;VanValkenburgh,Juno;Le,ThucM;Lok,Vincent;Hernandez,SelenaP;Song,Janet;Li,Joanna;Turlik,Aneta;Chen,Xiaohong;Cheng,Chi-An;Chen,Wei;Mona,ChristineE;Stuparu,An
一类基于异喹啉的α- n -杂环甲醛硫代氨基脲（HCT）化合物被重新发现；在此支架的基础上，通过反复的甲基化和氟化修饰，合成了三个系列的抗增殖剂，其抗癌活性因生理上相关的铜水平而增强。先导化合物HCT-13对一组胰腺癌、小细胞肺癌、前列腺癌和白血病模型有很强的抑制作用，IC50值在中低纳摩尔范围内。密度泛函理论（DFT）计算表明，HCT-13的6位氟化有利于配体-铜配合物的形成、稳定性和金属中心还原的便利性。通过化学基因组筛选，我们确定了DNA损伤反应/复制应激反应（DDR/RSR）途径，特别是由失调性毛细血管扩张和rad3相关蛋白激酶（ATR）介导的DNA损伤反应/复制应激反应（DDR/RSR）途径，作为HCT-13治疗后的潜在补偿机制。我们进一步表明，HCT-13的细胞毒性是铜依赖的，它促进线粒体电子传递链（mtETC）功能障碍，诱导活性氧（ROS）的产生，并选择性地耗尽鸟苷核苷酸库。最后，我们确定了治疗靶点分层的代谢标志，并证明了HCT-13对小鼠侵袭性急性白血病模型的体内疗效。
A potent class of isoquinoline-based α-N-heterocyclic carboxaldehyde thiosemicarbazone (HCT) compounds has been rediscovered; based upon this scaffold, three series of antiproliferative agents were synthesized through iterative rounds of methylation and fluorination modifications, with anticancer activities being potentiated by physiologically relevant levels of copper. The lead compound, HCT-13, was highly potent against a panel of pancreatic, small cell lung carcinoma, prostate cancer, and leukemia models, with IC50 values in the low-to-mid nanomolar range. Density functional theory (DFT) calculations showed that fluorination at the 6-position of HCT-13 was beneficial for ligand-copper complex formation, stability, and ease of metal-center reduction. Through a chemical genomics screen, we identify DNA damage response/replication stress response (DDR/RSR) pathways, specifically those mediated by ataxia-telangiectasia and Rad3-related protein kinase (ATR), as potential compensatory mechanism(s) of action following HCT-13 treatment. We further show that the cytotoxicity of HCT-13 is copper-dependent, that it promotes mitochondrial electron transport chain (mtETC) dysfunction, induces production of reactive oxygen species (ROS), and selectively depletes guanosine nucleotide pools. Lastly, we identify metabolic hallmarks for therapeutic target stratification and demonstrate the in vivo efficacy of HCT-13 against aggressive models of acute leukemias in mice.