99009-51-5Relevant academic research and scientific papers
Utilizing genome-wide mrna profiling to identify the cytotoxic chemotherapeutic mechanism of triazoloacridone C-1305 as direct microtubule stabilization
Baginski, Maciej,Bartoszewska, Sylwia,Bartoszewski, Rafal,Biernatowska, Agnieszka,Collawn, James F.,Crossman, David K.,Dudkowska, Magdalena,Janiszewska, Dorota,Króliczewski, Jaros?aw,Krzymiński, Karol,Markuszewski, Michal,Ochocka, Renata J.,Romanowska, Anna,Sikora, Ewa,Sikorski, Aleksander F.,Wysocka, Ma?gorzata
, (2020)
Rational drug design and in vitro pharmacology profiling constitute the gold standard in drug development pipelines. Problems arise, however, because this process is often difficult due to limited information regarding the complete identification of a molecule’s biological activities. The increasing affordability of genome-wide next-generation technologies now provides an excellent opportunity to understand a compound’s diverse effects on gene regulation. Here, we used an unbiased approach in lung and colon cancer cell lines to identify the early transcriptomic signatures of C-1305 cytotoxicity that highlight the novel pathways responsible for its biological activity. Our results demonstrate that C-1305 promotes direct microtubule stabilization as a part of its mechanism of action that leads to apoptosis. Furthermore, we show that C-1305 promotes G2 cell cycle arrest by modulating gene expression. The results indicate that C-1305 is the first microtubule stabilizing agent that also is a topoisomerase II inhibitor. This study provides a novel approach and methodology for delineating the antitumor mechanisms of other putative anticancer drug candidates.
Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors
Li, Zhi-Ying,Xu, Guang-Sen,Song, Yu-Liang,Li, Xun
, (2022/01/14)
Previously, an array of N-substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure–activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/β inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIβ subtypes.
Novel inhibitors of NRH:Quinone oxidoreductase 2 (NQO2): Crystal structures, biochemical activity, and intracellular effects of imidazoacridin-6-ones
Dunstan, Mark S.,Barnes, John,Humphries, Matthew,Whitehead, Roger C.,Bryce, Richard A.,Leys, David,Stratford, Ian J.,Nolan, Karen A.
experimental part, p. 6597 - 6611 (2011/12/01)
Imidazoacridin-6-ones are shown to be potent nanomolar inhibitors of the enzyme NQO2. By use of computational molecular modeling, a reliable QSAR was established, relating inhibitory potency with calculated binding affinity. Further, crystal structures of
1,8-NAPHTHALIMIDE IMIDAZO{4,5,1-DE}ACRIDONES WITH ANTI-TUMOR ACTIVITY
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, (2008/06/13)
The invention provides imidazoacridone compounds of general formula (1) which have cytotoxic and anti-tumor activity. The invention also provides methods of preparing the compounds, and methods of using the compounds for the treatment of cancer or other m
2-(Aminoalkyl)-5-nitropyrazoloacridines, a New Class of Anticancer Agents
Capps, David B.,Dunbar, James,Kesten, Suzanne R.,Shillis, Joan,Werbel, Leslie M.,et al.
, p. 4770 - 4778 (2007/10/02)
2-(Aminoalkyl)-5-nitropyrazoloacridines were prepared from substituted anilines via the 1-chloro-4-nitroacridones followed by condensation with hydrazines.Impressive activity was demonstrated for the 9-hydroxy, 9-alkoxy, and 9-acyloxy analogs in vitro on a L1210 leukemia line and in vivo against the P388 leukemia.Advanced studies led to the selection of 3bbb for clinical trial.
Substituted 1-amino-4-nitro-acridinones and methods of treating bacterial infections and leukemia with them
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, (2008/06/13)
Substituted 1-amino-4-nitroacridinones, their method of manufacture, pharmaceutical compositions and their use as antibacterial and antitumor agents are herein described.
Pyrazolo[3,4,5-kl]acridine compositions and methods for their production and use
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, (2008/06/13)
Pyrazolo[3,4,5-kl]acridines are described as antibacterial agents and antitumor agents as well as pharmaceutical compositions and methods for their preparation.
