Új, funkcionalizált peptidszármazékok előállítása és oldategyensúlyi vizsgálata = Synthesis and solution equilibrium studies of new, functionalised derivatives of peptides

A pályázat keretében 15 új peptidhidroxámsavat állítottunk elő és szisztematikusan megvizsgáltuk azt, hogy a ligandumok építőelemeinek (terminális aminocsoport jelenléte, a hidroxámsavcsoport nitrogénjének szubsztituense, a peptidlánc hossza, az oldalláncban jelenlevő erősen koordinálódni képes donorcsoport jelenléte) megváltoztatása hogyan befolyásolja fémionmegkötő képességüket. A ligandumok esszenciális (Fe3+, Cu2+, Ni2+, Zn2+, Mo(VI)) és toxikus (Al3+) fémionokkal való kölcsönhatásának tanulmányozására pH-potenciometriát, ESI-MS-t és spektrális módszereket (UV-VIS, NMR, CD, ESR) alkalmaztunk, meghatározva az oldatbeli részecskék összetételét, stabilitási szorzat értékeit és legvalószínűbb oldatszerkezetét. | Fifteen new peptide hydroxamic acids have been synthesized, characterized and a systematic study has been carried out to explore the effect of the change of the building blocks (presence of the terminal amino group, substituent at the nitrogen of the hydroxamic moiety, length of the peptide chain, presence of strongly coordinating donor in the side chain) of the ligands on their metal binding capability. The interaction of the peptide hydroxamic acids with essencial (Fe3+, Cu2+, Ni2+, Zn2+, Mo(VI)) and toxic (Al3+) metal ions has been studied using pH-potentiometry, ESI-MS and different spectroscopic (UV-VIS, NMR, CD, ESR) techniques

Interaction of folic acid and some matrix metalloproteinase (MMP) inhibitor folate-γ-hydroxamate derivatives with Zn(II) and human serum albumin

Human serum albumin binding of folic acid and its γ-hydroxamate/ carboxylate derivatives was studied by ultrafiltration and spectrofluorimetry, and it was found that the ligands exhibit a moderate binding (KD ∼ 2-50 μM), and the folate-γ-phenylalanine represents the highest conditional binding constant towards albumin. This feature may have importance in the serum transport processes of these ligands. Interaction of folic acid and its derivatives with Zn(II) was investigated in aqueous solution to obtain the composition and stabilities of the complexes by the means of pH-potentiometry, 1H NMR and electrospray ionization mass spectrometry, together with the characterization of the proton dissociation processes and the hydro-lipophilic properties of the ligands. The formation of mono-ligand complexes was demonstrated in all cases and the contribution of the glutamyl carboxylates to the coordination was excluded. Binding of folic acid and its γ-carboxylate derivatives to Zn(II) via the pteridine moiety is suggested, while the (O,O) coordination fashion of the folate-γ-hydroxamate ligands has importance in their inhibitory activity against Zn(II)-containing matrix metalloproteinases. It was found that the enzyme inhibition of these folate-γ-hydroxamate ligands is mainly tuned by other features, such as the lipophilic character rather than the Zn(II)-chelate stability. © 2010 Elsevier Inc. All rights reserved

Synthesis, characterization and albumin binding capabilities of quinizarin containing ternary cobalt(III) complexes

Four Co(III) ternary complexes with the composition of [(Co(4 N))2(quin)](ClO4)4 or [(Co(4 N))2(quinS)](ClO4)3, where 4 N = tris(2-aminoethyl)amine (tren) or tris(2-pyridylmethyl)amine (tpa), quinH2 = quinizarin (1,4-dihydroxy-9,10-anthraquinone), quinSH3 = quinizarin-2-sulfonic acid (1,4-dihydroxy-9,10-anthraquinone-2-sulfonic acid), were synthesized, characterized and their human serum albumin (HSA) binding capabilities were also tested. The complexes can be considered as likely chaperons of quinizarins which are structural models for anthracycline-based anticancer drugs like doxorubicin. All the Co(III) complexes are dinuclear and were isolated as mixture of isomers. Comparison of the cyclic voltammograms of the free ligands and the appropriate Co(III) complexes revealed that the new signals belonging to reversible processes in the range −400–0 mV (vs. Ag/AgCl) for the complexes can be attributed to the reversible reduction of the Co(III) centre. These potentials are in the range of typical (O,O) chelated Co(III) ternary complexes bearing 4 N donor ligands and follow the order being more positive for the tpa containing complexes. Presence of the sulfonate group in the quinizarin results in slightly more negative reduction potential of the Co(III) complexes. HSA binding capabilities of the quinH2 and quinSH3 ligands as well as the appropriate complexes showed that quinSH3 has higher affinity to the protein than quinH2 while none of the complexes seem to bind to HSA

PEGylation of surfacted magnetite core–shell nanoparticles for biomedical application

The surface of oleate double layer coated (surfacted) magnetite nanoparticles (OA@MNPs) was coated by PEG (poly(ethylene glycol) of Mw=1000, 4000 or 20,000Da, respectively, to get core-shell structured nanomagnets. The oleate bilayers were prepared in two different ways; (i) oleic acid was added directly into the magnetite co-precipitation mixture containing the MNPs to obtain OA@s-MNP samples - s-MNP standing for "as-synthesized MNP" and (ii) sodium oleate (oleate anion, OA) was added to the purified MNPs to obtain OA@p-MNP samples - p-MNP standing for "purified MNP". The effect of the surfactant addition method on the pH- and ionic strength-dependent stability (dynamic laser light scattering and laser-Doppler electrophoresis experiments), the biomedical applicability (MRI measurements) and the biocompatibility (blood sedimentation and blood smear tests) of the core-shell MNPs was studied. Different mechanisms of oleate adsorption were found in ATR FT-IR experiments (inner sphere surface complexation via ligand exchange for the s-MNPs and additional H-bonding for the p-MNPs), suggesting different behaviour. The colloidal stability and salt tolerance of the two kinds of OA@MNPs were similar, but the hydrodynamic diameter of the OA@s-MNP was considerably larger than that of OA@p-MNP. In accordance with this, the r2 relaxation was also higher for the s-MNP samples (~400 and ~200mM-1s-1, respectively). The physico-chemical tests indicate that the OA-coated MNPs form clusters and the degree of clustering of OA@s-MNPs is significantly greater than that of OA@p-MPNs. PEGylation does not appear to affect colloidal stability and salt tolerance meaningfully. The adsorption of PEG was proved experimentally. We have found that the PEG top layer decreases the electrostatic contribution, nevertheless increases the steric contribution of the original electrosteric stabilization caused by the OA double layer. However, an increase in the molecular weight above 1000Da and the amount of added PEG above 5mmol/g gradually reduces the salt tolerance of the samples. The results indicate strong potential for biomedical application and biocompatibility of the PEGylated MNPs

Hemocompatibility and Biomedical Potential of Poly(Gallic Acid) Coated Iron Oxide Nanoparticles for Theranostic Use

Polyacid covered core-shell iron oxide nanoparticles were designed for potential use in biomedicine with special attention to theranostics - magnetic resonance imaging (MRI), magnetic hyperthermia and magnetic drug targeting. The magnetite nanoparticles coated with a gallic acid shell polymerized in situ on the nanoparticle surface (PGA@MNPs) were tested for hemocompatibility in blood, sedimentation rate, blood smear and blood cell viability experiments and for antioxidant capacity in Jurkat cells in the presence of H2O2 as reactive oxygen species. No signs of interaction of the nanoparticles with whole blood cells were found. In addition, the PGA@MNPs reduced significantly the oxidative stress mediated by H2O2 supporting earlier findings of MTT tests, namely, the improvement of cell viability in their presence. The in vitro tests revealed that PGA@MNPs are not only biocompatible but also bioactive. Preliminary experiments revealed that the nanoparticles are especially efficient MRI and magnetic hyperthermia agents. The r2 relaxivity was found to be one of the highest among published values (387 mM-1s-1) and they possess a relatively significant specific absorption rate (SAR) value of 11 W/g magnetite