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.
Platinum(II) and Copper(II) complexes of asymmetric halogen-substituted [NN?O] ligands: Synthesis, characterization, structural investigations and antiproliferative activity
Amiri Rudbari, Hadi,Saadati, Arezoo,Aryaeifar, Mahnaz,Blacque, Olivier,Cuevas-Vicario, Jose V.,Cabral, Rui,Raposo, Luis R.,Fernandes, Alexandra R.
, (2021/12/27)
In order to better understand the effect of structure, halogen substitution, metal ions and ligand flexibility on antiproliferative activity, eight Cu(II) complexes and eight Pt(II) complexes were obtained of 2,4-X1,X2-6-((pyridine-2
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
Effects of tethered ligands and of metal oxidation state on the interactions of cobalt complexes with the 26S proteasome
Tomco, Dajena,Schmitt, Sara,Ksebati, Bashar,Heeg, Mary Jane,Dou, Q. Ping,Verani, Cláudio N.
experimental part, p. 1759 - 1766 (2012/04/17)
In this paper we report on the synthesis and characterization of three cobalt complexes described as [CoII(L1)2] (1), [CoII(L2)] (2), and [CoIII(L1) 2]ClO4 (3). These complexes contain the deprotonated forms of the [NN′O] tridentate ligand HL1 and its newly synthesized [N2N′2O2] hexadentate counterpart H 2L2, namely, 2,4-diiodo-6-((pyridine-2-ylmethylamino) methyl)phenol and 6,6′-((ethane-1,2-diylbis((pyridin-2-ylmethyl) azanediyl))bis(methylene))bis(2,4-diiodophenol). Characterizations for 1-3 include electrospray ionization (ESI) spectrometry, infrared, and UV-visible spectroscopies, and elemental analyses. A detailed 1H-NMR study was conducted for 3 and X-ray structural data was obtained for 2. The viability of this series as potential agents for proteasome inhibition and cell apoptotic induction involving PC-3 cancer cells is presented comparing the behavior of the untethered [NN′O]2 six-coordinate 1 and 3 and the tethered counterpart 2 with a 1:1 metal-to-ligand ratio. It is observed that the tethering in 2 decreases inhibition activity. When 1 and 3 are compared, the most inert, but redox-active, cobalt(III) species shows the highest chymotrypsin-like activity inhibition on purified proteasome and PC-3 cancer cells. A hypothesis based on the role of oxidation states for proteasome inhibition is offered.
