55474-90-3Relevant articles and documents
Quinazoline Ligands Induce Cancer Cell Death through Selective STAT3 Inhibition and G-Quadruplex Stabilization
?hlund, Daniel,Akhunzianov, Almaz,Br?nnstr?m, Kristoffer,Chand, Karam,Chorell, Erik,Deiana, Marco,Doimo, Mara,Hedenstr?m, Mattias,Jamroskovic, Jan,Kasho, Kazutoshi,Kumar, Rajendra,Mason, James E.,Medini, Paolo,Nath Das, Rabindra,Obi, Ikenna,Pourbozorgi, Parham L.,Sabouri, Nasim,Sulis Sato, Sebastian,Wanrooij, Sjoerd
, (2020/02/13)
The signal transducer and activator of transcription 3 (STAT3) protein is a master regulator of most key hallmarks and enablers of cancer, including cell proliferation and the response to DNA damage. G-Quadruplex (G4) structures are four-stranded noncanonical DNA structures enriched at telomeres and oncogenes' promoters. In cancer cells, stabilization of G4 DNAs leads to replication stress and DNA damage accumulation and is therefore considered a promising target for oncotherapy. Here, we designed and synthesized novel quinazoline-based compounds that simultaneously and selectively affect these two well-recognized cancer targets, G4 DNA structures and the STAT3 protein. Using a combination of in vitro assays, NMR, and molecular dynamics simulations, we show that these small, uncharged compounds not only bind to the STAT3 protein but also stabilize G4 structures. In human cultured cells, the compounds inhibit phosphorylation-dependent activation of STAT3 without affecting the antiapoptotic factor STAT1 and cause increased formation of G4 structures, as revealed by the use of a G4 DNA-specific antibody. As a result, treated cells show slower DNA replication, DNA damage checkpoint activation, and an increased apoptotic rate. Importantly, cancer cells are more sensitive to these molecules compared to noncancerous cell lines. This is the first report of a promising class of compounds that not only targets the DNA damage cancer response machinery but also simultaneously inhibits the STAT3-induced cancer cell proliferation, demonstrating a novel approach in cancer therapy.
Syntheses of Some New N-Linked Pyrimidine-2-amines with Pyrazinopyrimidines, Thienopyrimidines, and Benzazoles via Reactions of Various Nucleophiles with Cyanamides
Moustafa, Amr Hassan,Ahmed, Walaa Wefki,Khodairy, Ahmed
supporting information, p. 3490 - 3497 (2017/11/21)
New heterocycles containing 2-aminopyrimidine moiety linked with pyrazino[1,2-c]pyrimidines, thieno[2,3-d]pyrimidines, benzimidazoles, benzothiazoles, and benzoxazoles have been prepared by an efficient method starting from N-(pyrimidin-2-yl)cyanamides.
Microwave-expedited one-pot, two-component, solvent-free synthesis of functionalized pyrimidines
Goswami, Shyamaprosad,Jana, Subrata,Dey, Swapan,Kumar Adak, Avijit
, p. 120 - 123 (2008/02/11)
The synthesis of a series of diversely substituted pyrimidines under solvent-free conditions in good yields is described. Under microwave irradiation, a variety of nucleophilic substrates containing the N?C?N unit with ?-dicarbonyl compounds, ethyl cyanoacetate, malononitrile, and chalcones was cyclized to give pyrimidines. A combinatorial type approach for a one-step synthesis has been developed where a ring-closing condensation is followed by spontaneous aromatization to afford 28 functionalized and aryl/alkyl substituted pyrimidines. CSIRO 2007.
