908569-76-6Relevant articles and documents
Multifunctional Compounds for Activation of the p53-Y220C Mutant in Cancer
Miller, Jessica J.,Orvain, Christophe,Jozi, Shireen,Clarke, Ryan M.,Smith, Jason R.,Blanchet, Ana?s,Gaiddon, Christian,Warren, Jeffrey J.,Storr, Tim
, p. 17734 - 17742 (2018)
The p53 protein plays a major role in cancer prevention, and over 50 % of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA-binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53-Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53-Y220C surface cavity, and Zn-binding fragments for metallochaperone activity. Their Zn-binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53-Y220C-mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI-60), followed by testing in three stomach cancer cell lines with varying p53 status’, including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3-fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C-specific apoptosis in a cleaved caspase-3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild-type function in mutant p53-Y220C.
Dual anticancer and antibacterial activities of bismuth compounds based on asymmetric [NN'O] ligands
Marzano, Ivana M.,Tomco, Dajena,Staples, Richard J.,Lizarazo-Jaimes, Edgar H.,Gomes, Dawidson Assis,Bucciarelli-Rodriguez, M?nica,Guerra, Wendell,de Souza, ívina P.,Verani, Cláudio N.,Pereira Maia, Elene C.
, (2021/07/13)
Two new bismuth(III) complexes, [BiL1Cl2] (1) and [BiL2Cl2] (2), in which L1 is (2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine and L2 is 2,4-diiodo-6-((pyridine-2-ylmethylamino)me
