63127-04-8Relevant articles and documents
Targeting RNA polymerase I transcription machinery in cancer cells by a novel monofunctional platinum-based agent
Zhang, Zhen-Lei,Zhao, Chun-Lai,Chen, Qian,Xu, Kai,Qiao, Xin,Xu, Jing-Yuan
, p. 434 - 444 (2018)
Aberrant ribosome biogenesis and enlarged nucleoli have long been used by pathologists as a marker of aggressive tumors. Suppression of RNA polymerase I (Pol I) transcription machinery within the nucleolus could be a direct way to trigger the nucleolar stress and to inhibit the rapid proliferation of cancer cells. Here we modified cisplatin with an analogue of the selective inhibitor of RNA polymerase I-mediated transcription BMH-21 to develop a novel platinum-based Pol I selective inhibitor. We show that this novel monofunctional platinum-based agent, P1-B1, had enhanced antitumor activity of up to 17-fold greater than the clinical drug cisplatin in cisplatin-resistant non-small cell lung cancer cells. P1-B1 also had significantly lower cytotoxicity compared to cisplatin as well as the Pol I selective inhibitor BMH-21 in MRC-5 normal lung fibroblast cells, and the selectivity index (SI) greatly increases. Mechanistic investigations revealed that P1-B1 displayed significant nucleolar accumulation, selectively inhibited Pol I transcription, and induced nucleolar stress, leading to S-phase arrest and apoptosis. Our results suggest that the effects of P1-B1 are mechanistically distinct from those of conventional platinum agents and the recently described non-classical platinum compounds and that functionalizing platinum-based agents with directly Pol I transcription inhibition properties may represent an improved modality for cancer treatment.
Platinum-based compound based on nucleolar stress
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Paragraph 0042-0045, (2019/10/15)
The invention discloses a platinum-based compound based on nucleolar stress, wherein the platinum-based compound is a platinum-based antitumor compound formed by carrying out a nitrile-secondary amineClick reaction on cis-monochloro mononitrile diamino platinum and a primary amine-containing RNA polymerase I inhibitor. According to the present invention, the platinum-based antitumor compound hasgood RNA polymerase I inhibitory activity and good tumor selectivity, such that the platinum-based compound has antitumor activity suprior to classical platinum-based drugs, and can reduce toxic-sideeffects and overcome the drug resistance of clinical platinum-based drugs.
COMPOUNDS WHICH INHIBIT RNA POLYMERASE, COMPOSITIONS INCLUDING SUCH COMPOUNDS, AND THEIR USE
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Paragraph 0081; 0082, (2015/11/10)
RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.
Design, synthesis, and structure-activity relationships of pyridoquinazolinecarboxamides as RNA polymerase i inhibitors
Colis, Laureen,Ernst, Glen,Sanders, Sara,Liu, Hester,Sirajuddin, Paul,Peltonen, Karita,Depasquale, Michael,Barrow, James C.,Laiho, Marikki
, p. 4950 - 4961 (2014/07/07)
RNA polymerase I (Pol I) is a dedicated polymerase that transcribes the 45S ribosomal (r) RNA precursor. The 45S rRNA precursor is subsequently processed into the mature 5.8S, 18S, and 28S rRNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. On the basis of the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides have been evaluated as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. Structure-activity relationships in assays of nucleolar stress and cell viability demonstrate key pharmacophores and their physicochemical properties required for potent activation of Pol I stress and cytotoxicity. This work identifies a set of bioactive compounds that potently cause RPA194 degradation that function in a tightly constrained chemical space. This work has yielded novel derivatives that contribute to the development of Pol I inhibitory cancer therapeutic strategies.
Benzo-[g]pyrido[2,1-b]quinazolinones
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, (2008/06/13)
This invention relates to novel benzo- and tetrahydrobenzo-[f,g and h]pyrido[2,1-b]quinazolin-ones and their methods of preparation. These compounds have utility as antiallergy agents.
