Bidentate Ligands on Osmium(VI) Nitrido Complexes Control Intracellular Targeting and Cell Death Pathways
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† Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
‡ The Koch Institute for Integrative Cancer Research,Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
J. Am. Chem. Soc., Article ASAP
DOI: 10.1021/ja4075375
Publication Date (Web): August 20, 2013
Copyright © 2013 American Chemical Society
Abstract
The cellular response evoked by antiproliferating osmium(VI) nitrido compounds of general formula OsN(N^N)Cl3 (N^N = 2,2′-bipyridine 1, 1,10-phenanthroline 2, 3,4,7,8-tetramethyl-1,10-phenanthroline 3, or 4,7-diphenyl-1,10-phenanthroline 4) can be tuned by subtle ligand modifications. Complex 2 induces DNA damage, resulting in activation of the p53 pathway, cell cycle arrest at the G2/M phase, and caspase-dependent apoptotic cell death. In contrast, 4 evokes endoplasmic reticulum (ER) stress leading to the upregulation of proteins of the unfolded protein response pathway, increase in ER size, and p53-independent apoptotic cell death. To the best of our knowledge, 4 is the first osmium compound to induce ER stress in cancer cells.
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