Heterobimetallic Ru(μ-dppm)Fe and homobimetallic Ru(μ-dppm)Ru complexes as potential anti-cancer agents

Two heterobimetallic μ-dppm bridged Fe,Ru complexes, [(η6-Arene)RuCl2(μ-dppm)Fe(CO)I(η5-C5H5)] (Ar = C6H6 (1) and p-cymene (2), dppm = 1,1-bis(diphenylphosphino)methane) were obtained in a facile reaction between [Fe(η5-C5H5)I(CO)(κ1-dppm)] (5) and the corresponding [(η6-Arene)RuCl2]2 complexes by dimer cleavage, mediated by the pendant -PPh2 in 5. The homodinuclear Ru,Ru complex, [(η6-C6H6)RuCl2(μ-dppm)RuCl2(η6-C6H6)] (3), was also isolated in a straightforward fashion upon reaction of [(η6-C6H6)RuCl2(κ1-dppm)] (4) with [(η6-C6H6)RuCl2]2. All complexes were fully characterized by multinuclear (1H, 13C{1H}, 31P{1H}) NMR, UV–Vis, IR spectroscopy and HRMS (ESI), and additionally complex 3 was characterized by single crystal X-ray diffraction. Density functional theory (DFT) calculations (Level of theory B3LYP, basis set for H, C, P, O, N and Cl is 6-31 + G(d,p) and for Ru,Fe DGDZVP) of 1, 2 and 3 are also reported. Complexes 1 and 2 feature HOMOs and LUMOs delocalized over the iron-centered terminus of the bimetallic complexes. The cytotoxicity of 1–5 were evaluated on A2780 and A2780cisR (Human ovarian carcinoma) cell lines and the HEK293 (Human embryonic kidney) cell line. The complexes containing iron are more cytotoxic than cisplatin in the A2780 cells and significantly more active in the A2780cisR cell line and exhibit some selectivity towards the cancer cells. The dinuclear Ru,Ru complex 3 and the mononuclear complex 4 exhibit moderate activity on A2780 and A2780cisR cells also with some cancer cell selectivity. This study hence reveals the potential of Fe,Ru complexes as potent cytotoxic agents

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, α 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild-type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney. Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore, our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium