Inzulinutánzó fémkomplexek biospeciációja a sejten kívüli és a sejten belüli térben = Biospeciation of insulin-mimetic metal complexes in the extra intracellular space

Antidiabetikus, szájon át alkalmazható cink- és vanádiumkomplexek hatása összetett és a hatásmechanizmusuk csak részben feltárt az irodalomban. A fémkomplexek eredeti formája a metabolizmus során módosul, így a ténylegesen ható forma különbözik az alkalmazottól. A munka során számos potenciális inzulinutánzó cink- és vanádiumkomplex esetén feltártuk a lehetséges átalakulási folyamatokat. Vizsgáltuk az eredeti komplex vizes oldatbeli formáit is, meghatároztuk a képződő komplexek összetételét, stabilitását és pH-függő viselkedésüket, valamint hidro-lipofil sajátságukat. Részletesen tanulmányoztuk a sejtben nagy koncentrációban jelenlévő glutation és ATP vegyületekkel, valamint a vérszérum kis és nagy molekulatömegű alkotóival egyes cink-, ill. vanádiumkomplex vegyes ligandumú komplexképzését. Megállapítottuk, hogy leginkább a szérumfehérjéknek van hatása a fémkomplex eredeti formájának a megváltoztatásában, így a vérben való szállításukban is. A cink főképp az albuminhoz, a vanádium pedig a transzferrinhez kötődik. Vizsgálataink rámutattak arra is, hogy a komplexek szérumbeli eloszlásának értelmezéséhez igen fontos az eddig még ebben a körben nem vizsgált kölcsönhatás a humán szérum albumin és a hordozó ligandumok között. | Effect of antidiabetic, orally active zinc and vanadium complexes is quite complicated and not completely understood in the literature. Since the original form of the metal complexes is most probably modified during the metabolism, the actual active form of the complex may differ from the administrated solid compound. In the framework of the recent study possible transformation processes were investigated and revealed. The possible pH-dependence transformation of the original metal complex in aqueous solution was studied, stoichiometry, the stability and the hydro-lipophilic character of the complexes were determined. Detailed studies were performed on the mixed ligand complex formation processes of some insulin-mimetic metal complexes with relevant bioligands, such as cell constituents: glutathione and ATP, or low and high molecular mass serum components. It was concluded that serum proteins have dominant role in the transformation processes of the original form of the metal complexes and in their transport in the serum. Zinc is mostly bound to human serum albumin and vanadium to transferrin. Our results also drew the attention to the fact that for a better understanding of the biodistribution of the antidiabetic metal complexes in the blood and for the quantitative picture the interactions between human serum albumin and the carrier ligands have important role

Evaluation of In Vitro Distribution and Plasma Protein Binding of Selected Antiviral Drugs (Favipiravir, Molnupiravir and Imatinib) against SARS-CoV-2

There are a number of uncertainties regarding plasma protein binding and blood distribution of the active drugs favipiravir (FAVI), molnupiravir (MOLNU) and imatinib (IMA), which were recently proposed as therapeutics for the treatment of COVID-19 disease. Therefore, proton dissociation processes, solubility, lipophilicity, and serum protein binding of these three substances were investigated in detail. The drugs display various degrees of lipophilicity at gastric (pH 2.0) and blood pH (pH 7.4). The determined pKa values explain well the changes in lipophilic character of the respective compounds. The serum protein binding was studied by membrane ultrafiltration, frontal analysis capillary electrophoresis, steady-state fluorometry, and fluorescence anisotropy techniques. The studies revealed that the ester bond in MOLNU is hydrolyzed by protein constituents of blood serum. Molnupiravir and its hydrolyzed form do not bind considerably to blood proteins. Likewise, FAVI does not bind to human serum albumin (HSA) and α1-acid glycoprotein (AGP) and shows relatively weak binding to the protein fraction of whole blood serum. Imatinib binds to AGP with high affinity (logK′ = 5.8–6.0), while its binding to HSA is much weaker (logK′ ≤ 4.0). The computed constants were used to model the distribution of IMA in blood plasma under physiological and ‘acute-phase’ conditions as well

Új sziderofór modellek fémmegkötő sajátságainak vizsgálata: Hidroxámsavak és fémionok közötti kölcsönhatás szelektivitását befolyásoló tényezők = Studies on metal binding ability of new siderophore models: Factors affecting the interaction between hydroxamic acids and metal ions

A kutatás során (1) multikelátor típusú természetes sziderofórok (deszferrioxamin B és deszferrikoprogén) és analógok (pl. EDTA származék hidroxipiridinon), valamint modelljeik fémmegkötő sajátságainak, ezen belül a szelektivitást befolyásoló tényezőknek a vizsgálata, továbbá (2) a fémionokkal relatíve kisebb stabilítású kompexeket képező, "oldalláncukban" imidazolcsoportot tartalmazó új monohidroxámsavak előállítása és fémkomplexeiknek a tanulmányozása folyt. Az (1) témában több rendszernél is feltártuk a fémion-szelektivítást befolyásoló legfontosabb molekulaszerkezeti tényezőket. Bizonyítottuk és értelmeztük, hogy miért lehet pl. ólommérgezés esetén fémionkivonásra hatásosabb a DFC, mint a DFB. Egy lisszaboni laboratóriummal való együttműködésben néhány új hidroxipiridinon, pl. EDTA származék, fémkomplexeinek részletes oldategyensúlyi vizsgálata történt. Eredményeink szerint ezen ligandumok az M3+ és Mo(VI) fémionokat igen nagy hatékonysággal képesek komplexbe vinni, szelektíven kötni . (2) Számos imidazolcsoportot is tartalmazó új monohidroxámsav (mint potenciális metalloenzim inhibítor) előállítása és fémkomplexeik vizsgálata történt. Nemzetközi együttműködésben elindultak azok a vizsgálatok, melyek a monohidroxámsavaink metalloenzimek katalitikus centrumát modellező komplexekkel való kölcsönhatásának felderítésére irányulnak. | (1) Metal complexation of multichelator type natural siderophores (desferrioxamine B and desferricoprogen), their analogues (such as hydroxypyridinone derivative of EDTA) and some of their models have been investigated. Within this subject, characterization of the main factors determining the metal ion selectivity of these very effective metal binding agents was in the focus of the work. One of the most interesting results helped us to answer the question: Why can be the desferricoprogen a better lead-sequestering agent than desferrioxamine B' (2) Metal binding ability of potentially metalloenzyme inhibitor monohydroxamic acids has been also investigated. As a continuation of the previous work, the effect of the imidazole situating in various distances compared to the hydroxamic function was studied. Following the examination of the binary systems, the interaction of the imidazole containing monohydroxamic acids with model complexes for catalytic centre of metalloenzymes is planned to study nowadays

Speciation of metal complexes of medicinal interest: relationship between solution equilibria and pharmaceutical properties

Biospeciation of essential and toxic metal ions, metal complexes with biological or medicinal activity are discussed in the paper in order to emphasize the importance of the distribution of metal ions in biological milieu. The exact knowledge of the chemical species present in the different organs/compartments/fluids/cells may provide essential information about the pharmacokinetic properties and the biological effect of the metal ion or the drug candidate metal complex. The transport of essential and toxic metal ions in the blood serum is discussed first, which is followed by the description of biodistribution of several important metal complexes with medicinal interest such as (i) anticancer, (ii) insulin-enhancing and (iii) MRI contrast agents in biological fluids

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