title: Synthesis, spectroscopic and DFT structural characterization of two novel ruthenium(III) oxicam complexes. In vivo evaluation of anti-inflammatory and gastric damaging activities.
abstract: The reactions of ruthenium(III) chloride trihydrate with piroxicam (H2PIR) and tenoxicam (H2TEN), two widely used non-steroidal anti-inflammatory drugs, afforded [Ru(III)Cl2(H2PIR)(HPIR)],·1, and [Ru(III)Cl2(H2TEN)(HTEN)],·2. Both compounds were obtained as pure green solids through purification via flash column chromatography. Characterizations were accomplished through UV-vis and IR spectroscopy, potentiometry and HPLC. Quantum mechanics and density functional computational methods were applied to investigate their respective molecular structures. The experimental and computational results are in agreement with a pseudo-octahedral coordination where the two chlorido ligands are in trans positions (apical) and the two trans-N,O chelating oxicam ligands occupy the equatorial sites. Both compounds revealed an acceptable solubility and stability profile upon dissolution in a standard buffer at physiological pH. Nonetheless, the addition of biologically occurring reducing agents caused spectral changes. The two complexes manifested a poor reactivity with the model proteins cytochrome c and lysozyme: no evidence for adduct formation was indeed obtained based on a standard ESI MS analysis; in contrast, some significant reactivity with serum albumin was proved spectrophotometrically. Remarkably, both study compounds revealed pronounced anti-edema effects in vivo suggesting that the pharmacological actions of the ligands are mostly retained; in addition, they were less irritating than piroxicam on the gastric mucosa when the coordination compounds and free oxicam were administered at the same overall molar concentration of the ligand. Overall, the present results point out that ruthenium coordination may represent an effective strategy to improve the pharmacological properties of oxicam drugs reducing their undesired side effects.
authors: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy. Electronic address: tamasi@unisi.it.
authors: Gabriella
authors: G
authors: Tamasi
authors: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Caterina
authors: C
authors: Bernini
authors: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Gianfranco
authors: G
authors: Corbini
authors: Department of Chemistry, Emory University, Atlanta, GA, USA.
authors: Natalie F
authors: NF
authors: Owens
authors: Laboratory of Metals in Medicine METMED, Department of Chemistry, University of Florence, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy.
authors: Luigi
authors: L
authors: Messori
authors: Laboratory of Metals in Medicine METMED, Department of Chemistry, University of Florence, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy.
authors: Federica
authors: F
authors: Scaletti
authors: Laboratory of Metals in Medicine METMED, Department of Chemistry, University of Florence, Via della Lastruccia 3, I-50019 Sesto Fiorentino, Florence, Italy.
authors: Lara
authors: L
authors: Massai
authors: Sigma-tau S.p.A., R&D Department, Via Pontina km 30.400, Pomezia, Roma, Italy.
authors: Pietro Lo
authors: PL
authors: Giudice
authors: Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Via Aldo Moro 2, I-53100 Siena, Italy.
authors: Renzo
authors: R
authors: Cini
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045304:Cytochromes c / Q000737:chemistry; D004355:Drug Stability; D004487:Edema / Q000188:drug therapy*; D006614:Hindlimb; D006801:Humans; D008024:Ligands; D008297:Male; D009113:Muramidase / Q000737:chemistry; D010894:Piroxicam / Q000031:analogs & derivatives* / Q000737:chemistry*; D011485:Protein Binding; D011789:Quantum Theory; D051381:Rats; D017208:Rats, Wistar; D017975:Ruthenium Compounds / Q000737:chemistry*; D012709:Serum Albumin / Q000737:chemistry; D012995:Solubility
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D056831:Coordination Complexes; D008024:Ligands; D017975:Ruthenium Compounds; D012709:Serum Albumin; D010894:Piroxicam; D045304:Cytochromes c; D009113:Muramidase; C038365:ruthenium chloride; C032801:tenoxicam
keywords: Anti-cancer drugs; Anti-inflammatory drugs; Density functional; Ruthenium complexes; Spectroscopy