Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias,RSC Medicinal Chemistry

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Isoquinoline thiosemicarbazone displays potent anticancer activity with in vivo efficacy against aggressive leukemias
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2020-02-24 , DOI: 10.1039/c9md00594c
Daniel L Sun _{1,

2,

3} , Soumya Poddar _{1,

2} , Roy D Pan _{1,

2,

3} , Ethan W Rosser _{1,

2,

3} , Evan R Abt _{1,

2} , Juno Van Valkenburgh _{1,

2,

3} , Thuc M Le _{1,

2} , Vincent Lok ₁ , Selena P Hernandez ₃ , Janet Song ₁ , Joanna Li ₁ , Aneta Turlik ₃ , Xiaohong Chen ₃ , Chi-An Cheng _{3,

4} , Wei Chen ₃ , Christine E Mona _{1,

2} , Andreea D Stuparu _{1,

2} , Laurent Vergnes ₅ , Karen Reue _{5,

6} , Robert Damoiseaux ₇ , Jeffrey I Zink ₃ , Johannes Czernin _{1,

2} , Timothy R Donahue _{1,

2,

8} , Kendall N Houk ₃ , Michael E Jung ₃ , Caius G Radu _{1,

2}

Affiliation

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.

中文翻译：

异喹啉缩氨基硫脲显示出有效的抗癌活性和体内对抗侵袭性白血病的功效

重新发现了一类有效的基于异喹啉的 α-N-杂环甲醛缩氨基硫脲 (HCT) 化合物；基于这种支架，通过甲基化和氟化修饰的迭代轮次合成了三个系列的抗增殖剂，其中生理相关水平的铜增强了抗癌活性。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非常有效，IC ₅₀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容易性。通过化学基因组学筛选，我们确定了 DNA 损伤反应/复制应激反应 (DDR/RSR) 通路，特别是由共济失调毛细血管扩张症和 Rad3 相关蛋白激酶 (ATR) 介导的通路，作为HCT 后的潜在补偿机制-13治疗。我们进一步表明HCT-13的细胞毒性是铜依赖性的，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，并选择性地消耗鸟苷核苷酸库。最后，我们确定治疗靶分层代谢标志和证明在体内的功效HCT-13对抗小鼠急性白血病侵袭性模型。

更新日期：2020-02-24

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