Cyclometalated Iron(II) Complexes Induce The Endoplasmic Reticulum Stress Pathway and Ferroptosis in Gastric Cancer Cells

High Resolution Image Download MS PowerPoint Slide A series of cyclometalated iron(II) complexes of the general formula [Fe II (ĈN)(N̂N) 2 ]PF 6, where HĈN = 2-phenylpyridine (phpyH) or 7,8-benzoquinoline (bzqH) and N̂N = 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen), has been synthesized by reacting [Fe 2 (CO) 9 ] with the selectively brominated derivatives of phpyH and bzqH, namely, phpyBr or bzqBr, followed by substitution reactions with diimine ligands (bpy or phen). The structures have been confirmed by X-ray diffraction crystallography, NMR, UV–vis spectroscopy, and cyclic voltammetry. Compared to cisplatin and oxaliplatin, complexes 3 (ĈN = phpy/N̂N = phen), 4 ĈN = bzq/N̂N = bpy), and 5 (ĈN = bzq/N̂N = phen) exhibited superior cytotoxicity in two gastric cancer cell lines, and complex 2 (ĈN = phpy/N̂N = bpy) was almost nontoxic on a noncancerous cell line. At the molecular level, the compounds activate ER stress pathway effectors (ATF4 and CHOP) while inhibiting GP x 4 expression, suggesting induction of ferroptosis. This study highlights the broad potential for anticancer applications of new cyclometalated compounds based on earth-abundant iron, which are more affordable and environmentally friendly than their ruthenium and osmium counterparts.