Seven rhenium(I) complexes of the general formula fac-[Re(CO)3(NN)(OH2)]+ where NN = 2,2′-bipyridine (8), 4,4′-dimethyl-2,2′-bipyridine (9), 4,4′-dimethoxy-2,2′-bipyridine (10), dimethyl 2,2′-bipyridine-4,4′-dicarboxylate (11), 1,10-phenanthroline (12), 2,9-dimethyl-1,10-phenanthroline (13), or 4,7-diphenyl-1,10-phenanthroline (14), were synthesized and characterized by 1H NMR spectroscopy, IR spectroscopy, mass spectrometry, and X-ray crystallography. With the exception of 11, all complexes exhibited 50% growth inhibitory concentration (IC50) values that were less than 20 μM in HeLa cells, indicating that these compounds represent a new potential class of anticancer agents. Complexes 9, 10, and 13 were as effective in cisplatin-resistant cells as wild-type cells, signifying that they circumvent cisplatin resistance. The mechanism of action of the most potent complex, 13, was explored further by leveraging its intrinsic luminescence properties to determine its intracellular localization. These studies indicated that 13 induces cytoplasmic vacuolization that is lysosomal in nature. Additional in vitro assays indicated that 13 induces cell death without causing an increase in intracellular reactive oxygen species or depolarization of the mitochondrial membrane potential. Further studies revealed that the mode of cell death does not fall into one of the canonical categories such as apoptosis, necrosis, paraptosis, and autophagy, suggesting that a novel mode of action may be operative for this class of rhenium compounds. The in vivo biodistribution and metabolism of complex 13 and its 99mTc analogue 13* were also evaluated in naı̈ve mice. Complexes 13 and 13* exhibited comparable biodistribution profiles with both hepatic and renal excretion. High-performance liquid chromatography inductively coupled plasma mass-spectrometry (HPLC-ICP-MS) analysis of mouse blood plasma and urine postadministration showed considerable metabolic stability of 13, rendering this potent complex suitable for in vivo applications. These studies have shown the biological properties of this class of compounds and demonstrated their potential as promising theranostic anticancer agents that can circumvent cisplatin resistance.

The mixed-valent oxo-bridged ruthenium complex [(HCO2)(NH3)4Ru(μ-O)Ru(NH3)4(O2CH)]3+, known as Ru360, is a selective inhibitor of mitochondrial calcium uptake. Although this compound is useful for studying the role of mitochondrial calcium in biological processes, its widespread availability is limited because of challenges in purification and characterization. Here, we describe our investigations of three different synthetic methods for the preparation of a functional analogue of this valuable compound. We demonstrate that this analogue, isolated from our procedures, exhibits potent mitochondrial calcium uptake inhibitory properties in permeabilized HeLa cells and in isolated mitochondria.

•A new hydroxy-azobenzene ligand was synthesized.•Three new platinum(II) compounds were prepared and characterized.•These complexes are not photoreactive.•The platinum complexes are anticancer active against cisplatin-resistant cells.•The platinum complexes weakly interact with DNA.The syntheses of three platinum(II) complexes bearing sulfonamide- ( (E)-2-(4-methylphenylsulfonamido)-2′,6′-difluoroazobenzene, HL1) and hydroxy-azo-2,6-difluorobenzene ((E)-2-((2,6-difluorophenyl)diazenyl)phenol, HL2) bidentate ligands is described. These complexes, [Pt(L1)(DMSO)Cl] (1), [Pt(L2)(DMSO)Cl] (2), and [Pt(L2)2] (3), were characterized by multinuclear NMR spectroscopy, mass spectrometry, and X-ray crystallography. Despite bearing azobenzene functional groups, none of the three complexes undergo photoisomerization. The anticancer activities of these complexes were evaluated in wild-type (A2780) and cisplatin-resistant (A2780CP70) ovarian cancer cells. All three complexes exhibited IC50 values below 10 μM and displayed similar activity in both A2780 and A2780CP70 cell lines, indicating that they are not cross-resistant with cisplatin. The DNA-binding properties of 1–3 were investigated by circular dichroism spectroscopy and by agarose gel electrophoresis. Both studies suggest that 1 and 2 form monofunctional DNA adducts.Synopsis: Three platinum(II) complexes bearing hydroxy- and sulfonamide-azobenzene ligands were synthesized and characterized. These new compounds exhibit potent anticancer activity against both wild-type and cisplatin-resistant ovarian cancer cells.Download high-res image (231KB)Download full-size image

•A new hydroxy-azobenzene ligand was synthesized.•Three new platinum(II) compounds were prepared and characterized.•These complexes are not photoreactive.•The platinum complexes are anticancer active against cisplatin-resistant cells.•The platinum complexes weakly interact with DNA.The syntheses of three platinum(II) complexes bearing sulfonamide-((E)-2-(4-methylphenylsulfonamido)-2′,6′-difluoroazobenzene, HL1) and hydroxy-azo-2,6-difluorobenzene ((E)-2-((2,6-difluorophenyl)diazenyl)phenol, HL2) bidentate ligands is described. These complexes, [Pt(L1)(DMSO)Cl] (1), [Pt(L2)(DMSO)Cl] (2), and [Pt(L2)2] (3), were characterized by multinuclear NMR spectroscopy, mass spectrometry, and X-ray crystallography. Despite bearing azobenzene functional groups, none of the three complexes undergo photoisomerization. The anticancer activities of these complexes were evaluated in wild-type (A2780) and cisplatin-resistant (A2780CP70) ovarian cancer cells. All three complexes exhibited IC50 values below 10 μM and displayed similar activity in both A2780 and A2780CP70 cell lines, indicating that they are not cross-resistant with cisplatin. The DNA-binding properties of 1–3 were investigated by circular dichroism spectroscopy and by agarose gel electrophoresis. Both studies suggest that 1 and 2 form monofunctional DNA adducts.Synopsis: Three platinum(II) complexes bearing hydroxy- and sulfonamide-azobenzene ligands were synthesized and characterized. These new compounds exhibit potent anticancer activity against both wild-type and cisplatin-resistant ovarian cancer cells.Download high-res image (233KB)Download full-size image

Reactions of K3[Ru2NCl8(H2O)2] with 2,2′-bipyridine (bpy), 4,4′-dimethyl-2,2′-bipyridine (dmbpy), and 4,4′-dimethoxy-2,2′-bipyridine (dmobpy) yielded the nitrido-bridged dinuclear complexes [Ru2N(L)2Cl5(DMF)] where L = bpy (1), dmbpy (2), and dmobpy (3). The crystal structures of these complexes reveal a linear Ru–N–Ru moiety with each ruthenium center bearing a bidentate diimine ligand. The complexes were further characterized by NMR, IR, and UV-vis spectroscopic methods and cyclic voltammetry. Because the compounds bear some structural similarities with the mitochondrial calcium uptake inhibitor Ru360, the ability of these complexes to act in this capacity was evaluated. The results demonstrate that 1–3 all fail to block mitochondrial calcium uptake, revealing new facets of the structure–activity relationships for ruthenium-based mitochondrial calcium uptake inhibitors.

AbstractThe 18-membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all 225Ac (26 kBq) in 5 min at RT. [225Ac(macropa)]+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa-NCS, was conjugated to trastuzumab as well as to the prostate-specific membrane antigen-targeting compound RPS-070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa-Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac-macropa-RPS-070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft-tissue metastases.