Synthesis, structural and spectroscopic characterization, in vitro cytotoxicity and in vivo activity as free radical scavengers of chlorido( p-cymene) complexes of ruthenium(II) containing N-alkylphenothiazines

• Published in: European journal of medicinal chemistry 2011-09, Vol.46 (9), p.4168-4177
• Main Authors: Krstić, Milena, Sovilj, Sofija P., Grgurić-Šipka, Sanja, Evans, Ivana Radosavljević, Borozan, Sunčica, Santibanez, Juan Francisco
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antioxidant enzymes; Biological and medical sciences; Cell Line, Tumor; Crystallography, X-Ray; Cytotoxicity; Drug Screening Assays, Antitumor; Free Radical Scavengers - chemical synthesis; Free Radical Scavengers - chemistry; Free Radical Scavengers - pharmacology; General aspects; Humans; Magnetic Resonance Spectroscopy; Male; Medical sciences; Models, Molecular; Molecular Structure; Monoterpenes - chemistry; N-Alkylphenothiazines; p-Cymene; Pharmacology. Drug treatments; Phenothiazines - chemistry; Rats; Rats, Wistar; Ruthenium complexes; Ruthenium Compounds - chemistry; Single crystal X-ray diffraction; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.06.019

Three new ruthenium(II) complexes 1– 3 containing N-alkylphenothiazine molecules were synthesized by reaction of [RuCl 2(η 6- p-cymene)] 2 with chlorpromazine hydrochloride ( 1), trifluoperazine dihydrochloride ( 2) or thioridazine hydrochloride ( 3). The compounds of the general formula L[RuCl 3(η 6- p-cymene)] were characterized by elemental analysis and spectroscopic methods (FT-IR, UV–Vis, 1H and 13C NMR). Complex 2 was structurally characterized by single crystal X-ray diffraction. In vitro cytotoxic activity of complexes 1– 3 were assayed in four human carcinoma cell lines MCF-7, MDA-MB-453 (breast carcinoma), SW-480 (colon carcinoma) and IM9 (myeloma multiple cells). The highest cytotoxicity (12.1 ≤ IC 50 ≤ 17.3 μM) and induced a total (SW-480) or almost total cell death (MCF-7, MDA-MB-453) at 25 μM in 48 h of treatment were observed for complex 2. The influence of three different doses (0.4, 4.5 and 90.4 μM/kg bw) of complex 2 on activities of antioxidants enzymes (superoxide dismutase (SOD) and catalase (CAT)) and lactate dehydrogenase (LDH) were investigated under physiological conditions. The effects on nitrite production ( NO 2 − ) and level of erythrocytes malondialdehyde (MDA) in rats blood were evaluated, too. Ruthenium(II)-arene complexes with N-alkylphenothiazine were synthesized and characterized. In vitro cytotoxic effects in four human carcinoma cell lines and in vivo enzyme activity of the complexes were observed. [Display omitted] ► The chlorido( p-cymene) complexes of ruthenium(II) with N-alkylphenothiazines were synthesized. ► Complex with trifluoperazine ( 2) was characterized by single crystal X-ray diffraction. ► Complex 2 showed the highest antiproliferative effects in four human carcinoma cell lines. ► Complex 2 inhibited antioxidant enzymes activities. ► The positive effect was shown on the heart muscle by reducing the level of LDH 2 isoenzymes.