Synthesis, Characterization, and Cytotoxicity of Morpholine-Containing Ruthenium(II) p-Cymene Complexes

Abstract

Morpholine motif is an important pharmacophore and, depending on the molecular design, may localize in cellular acidic vesicles. To understand the importance of the presence of pendant morpholine in a metal complex, six bidentate N,O-donor ligands with or without a pendant morpholine unit and their corresponding ruthenium­(II) p-cymene complexes (1–6) are synthesized, purified, and structurally characterized by various analytical methods including X-ray diffraction. Complexes 2–4 crystallized in the P21/c space group, whereas 5 and 6 crystallized in the P1̅ space group. The solution stability studies using 1H NMR support instantaneous hydrolysis of the native complexes to form monoaquated species in a solution of 3:7 (v/v) dimethyl sulfoxide-d 6 and 20 mM phosphate buffer (pH* 7.4, containing 4 mM NaCl). The monoaquated complexes are stable for at least up to 24 h. The complexes display excellent in vitro antiproliferative activity (IC50 ca. 1–14 μM) in various cancer cell lines, viz., MDA-MB-231, MiaPaCa2, and Hep-G2. The presence of the pendant morpholine does not improve the dose efficacy, but rather, with 2-[[(2,6-dimethylphenyl)­imino]­methyl]­phenol (HL1) and its pendant morpholine analogue (HL3) giving complexes 1 and 3, respectively, the antiproliferative activity was poorer with 3. MDA-MB-231 cells treated with the complexes show that the acidic vesicles remain acidic, but the population of acidic vesicles increases or decreases with time of exposure, as observed from the dispersed red puncta, depending on the complex used. The presence of the 2,6-disubstituted aniline and the naphthyl group seems to improve the antiproliferative dose. The complex treated MDA-MB-231 cells show that cathepsin D, which is otherwise present in the cytosolic lysosomes, translocates to the nucleus as a result of exposure to the complexes. Irrespective of the presence of a morpholine motif, the complexes do not activate caspase-3 to induce apoptosis and seem to favor the necrotic pathway of cell killing.

A highly active and chemoselective homobimetallic ruthenium catalyst for one-pot reductive amination in water

“…[62][63][64] Complexes Ru1 and Ru2 were prepared in high yields by modifying a reported procedure. 65,66 Their typical synthesis involves the reactions between [Ru( p-cymene)(μ-Cl)Cl] 2 and salicylaldimine H 2 L 1 or HL 2 in the presence of potassium carbonate as a base in ethanol at room temperature (Scheme 3). Crude products pre- cipitate out as dark red solids which were recrystallized from the dichloromethane : ethanol (4 : 1 v/v) mixture.…”

Morpholine-modified Ru-based agents with multiple antibacterial mechanisms as metalloantibiotic candidates against Staphylococcus aureus infection

“…18 Notably, morpholine-modied agents exhibited a wide range of biological properties, including anti-inammatory, antioxidant, antibacterial, and antitumor activities. 19,20 In various antibiotics, the morpholine moiety also has an important effect on their antibacterial activity (Scheme 1A). 17 Herein, in order to screen a promising metalloantibiotic with a multitarget mechanism and robust potency, we introduced a morpholine moiety into an Ru-based structure and then obtained a series of novel Ru-based antibacterial agents (Scheme 1B).…”

“…18 Notably, morpholine-modified agents exhibited a wide range of biological properties, including anti-inflammatory, antioxidant, antibacterial, and antitumor activities. 19,20 In various antibiotics, the morpholine moiety also has an important effect on their antibacterial activity (Scheme 1A). 17…”