- Preparation method of formaldehyde-substituted aza-condensed ring compound
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The invention provides a preparation method of a formaldehyde-substituted aza-condensed ring compound, comprising the following steps: by using an aza-condensed ring lactam compound as a starting material, carrying out halogenation reaction, methylation reaction and methyl oxidation reaction to obtain the formaldehyde-substituted aza-condensed ring compound. According to the preparation method ofthe formaldehyde-substituted aza-condensed ring compound, the whole synthesis route is good in step repeatability, mild in operation condition and high in safety, and large-scale production and industrial popularization are facilitated; post-treatment energy consumption is low, a large amount of toxic wastewater is not generated, no pollution is caused to the environment, the production safety level and the production cost are reduced, application of green and environment-friendly industrial production is facilitated, and wide application prospects are achieved.
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- Isoquinoline thiosemicarbazone displays potent anticancer activity with: In vivo efficacy against aggressive leukemias
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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.
- Sun, Daniel L.,Poddar, Soumya,Sun, Daniel L.,Pan, Roy D.,Poddar, Soumya,Rosser, Ethan W.,Pan, Roy D.,Abt, Evan R.,Rosser, Ethan W.,Van Valkenburgh, Juno,Abt, Evan R.,Le, Thuc M.,Van Valkenburgh, Juno,Lok, Vincent,Le, Thuc M.,Song, Janet,Li, Joanna,Hernandez, Selena P.,Mona, Christine E.,Stuparu, Andreea D.,Czernin, Johannes,Turlik, Aneta,Donahue, Timothy R.,Chen, Xiaohong,Radu, Caius G.,Cheng, Chi-An,Hernandez, Selena P.,Chen, Wei,Mona, Christine E.,Stuparu, Andreea D.,Vergnes, Laurent,Reue, Karen,Damoiseaux, Robert,Zink, Jeffrey I.,Czernin, Johannes,Donahue, Timothy R.,Houk, Kendall N.,Jung, Michael E.,Radu, Caius G.
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p. 392 - 410
(2020/04/15)
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- NNYTHIOSEMICARBAZONE COMPOUNDS AND USES THEREOF
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Provided, inter alia, are thiosemicarbazone compounds, metal complexes of thi osemi carb azone compounds, pharmaceutical compositions, and methods for treating cancer.
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Paragraph 0407-0408; 0429
(2020/09/12)
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