V^IVO complexes with antibacterial quinolone ligands and their interaction with serum proteins

Abstract

Quinolone derivatives are among the most commonly prescribed antibacterials in the world and could also attract interest as organic ligands in the design of metal complexes with potential pharmacological activity. In this study, five compounds, belonging to the first (nalidixic acid or Hnal), second (ciprofloxacin or Hcip, and norfloxacin or Hnor) and third generation (levofloxacin or Hlev, and sparfloxacin or Hspar) of quinolones, were used as ligands to bind the VO ion. In aqueous solution, mono- and bis-chelated species were formed as a function of pH, with cis-[VOHL(HO)] and [VOHL], x = 0-2, being the major complexes at pH 7.4. DFT calculations indicate that the most stable isomers are the octahedral OC-6-32 and the square pyramidal SPY-5-12, in equilibrium with each other. To the best of our knowledge, this is the first case that an equilibrium between a penta-coordinated square pyramidal complex and a hexa-coordinated octahedral complex is observed in solution for ligands forming six-membered chelated rings. Nalidixic acid forms the solid compound [VO(nal)(HO)], to which a cis-octahedral geometry was assigned. The interaction with 1-methylimidazole (MeIm) causes a shift of the equilibrium SPY-5 + HO ⇄ OC-6 toward the right after the formation of cis-[VOHL(MeIm)], where MeIm replaces an equatorial water ligand. The study of the systems containing [VO(nal)(HO)] and the serum proteins - albumin (HSA), apo-transferrin (apo-hTf) and holo-transferrin (holo-hTf) - indicates that HSA and holo-hTf form the mixed species {VO(nal)}(HSA) and {VO(nal)}(holo-hTf), where y = 1-3 denotes the number of VO(nal) moieties bound to accessible histidines (His105, His367, His510 for HSA, and His25, His349, His606 for holo-hTf), whereas apo-hTf yields VO(nal)(apo-hTf) with the coordination of the His289 residue only. Docking calculations suggest that the specific conformation of apo-hTf and the steric hindrance of the cis-VO(nal) moiety interfere with its interaction with all the surface His residues and the formation of a hydrogen bond network which could stabilize the binding sites.

Thermodynamic Study of Oxidovanadium(IV) with Kojic Acid Derivatives: A Multi-Technique Approach

“…with the two V IV O 2+ ions in an octahedral geometry and water ligand in cis to the V=O bond, a typical arrangement for KA derivatives [56][57][58]. The lacking detection of two water molecules in the mass spectra is in line with the results in the literature since it has been demonstrated that a weak monodentate ligand can be removed from the metal coordination sphere during the ionization process [59][60][61].…”

Vanadium in Biological Action: Chemical, Pharmacological Aspects, and Metabolic Implications in Diabetes Mellitus

“…Albumin plays a major role in the transport of metals in the plasma. Structurally the protein contains two metal binding sites, an N-terminal site (NTS or site I) that specifically binds Cu +2 and Ni +2 ions, and a multimetal binding site (MBS or site II) that primary binds Zn +2 ions but also displays high affinity for Cu +2 and Ni +2 ions [94, 115–119]. As for the interaction of the protein with vanadium, particularly the VO 2+ species, studies have identified a high-affinity binding site (VBS1) and at least five relatively low-affinity vanadium binding sites (VBS2) [94, 120, 121].…”

“…The contents of vanadium in plasma, decline in three phases: (i) The first phase is a rapid decline with a half-life of about 1 h, followed by (ii) a second intermediate phase where vanadium decline with a half-life ca 26 h, and moreover, (iii) a third slow phase where, on average, the half-life is approximately 10 days. Vanadium contents in blood are thus reduced to about 30% within the first 24 h, and about 50% is recovered in urine after 12 days [106, 115, 135]. Although the body clearance occurs directly via urinary excretion, while as long as the vanadium stays in the bloodstream, the distribution occurs towards different tissues such as the heart, liver, kidney, spleen, brain, muscle, adipose tissue, and bones.…”

“…In this context, vanadium is found naturally in horse spleen ferritin at levels of 5 to 10 vanadium atoms per protein, and interestingly, it exhibits a pH dependence with decreasing VO 2+ /protein ratios as the pH increases (e.g., 61%, 36%, and 27% at pH 6, 7, and 8, respectively), using a ratio VO 2+ /protein of 16 [88, 93, 197]. By using EPR spectroscopy, V +5 and V 4+ species were detected in rats fed under vanadium-rich diets, particularly in the ferritin proteins from the liver, kidney, and spleen [113, 115, 198]. The EPR experiments indicate that the signals arise from the complex formed in the ferritin’s interior between iron and the VO 2+ species.…”

Vanadium in the environment as a risk factor causing negative modification of cell death (scientific review) UDC: 616-097

“…Попав в системный кровоток, ванадий связывается с белками плазмы, в частности с трансферрином и альбумином, низкомолекулярными лигандами, такими как цитрат, оксалат, лактат, фосфат, глицин, гистидин, а также с гемоглобином, и при высоких концентрациях -с иммуноглобулином G [6,8,24,25]. В течение первых 24 ч после проникновения в организм содержание ванадия в крови снижается примерно на 30 % [26]. Между тем способность ванадатов заменять фосфаты в костной ткани приводит к накоплению и длительному сохранению ванадия в костях -более месяца [27].…”