Helatacione osobine liganada EDTA-tipa u odnosu na bakar(II) - moguća primena kod neurotoksičnih poremećaja

IZVOD: Poliaminopolikarboksilatni helati (APK) poslednjih nekoliko godina nalaze izuzetnu primenu u detoksifikaciji organizma uzrokovanoj teškim metalima, u lečenju infekcija, kardiovaskularnih i nervnih oboljenja. Posedovanjem šest donorskih atoma APK kiseline ostvaruju izuzetnu sposobnost helatacije metalnih jona. Polazeći od ovih činjenica za predmet ove disertacije predviđena je sinteza APK kiselina etilendiaminskog (E-APK) i propandiaminskog (P-APK) tipa kao i njihove interakcije sa jonima bakra(II) i bakra(I). Karakterizacija sintetisanih jedinjenja izvršena je upotrebom najsavremenijih metoda kao što su spektroskopija (UV-vis, IR), elektronska paramagnetna rezonanca (EPR), elektrohemija kao i kompjuterska hemija. Strukture dva kompleksa: Ba[Cu(1,3-pd3ap)]6H2O (trigonalno-bipiramidalna geometrija) i trans(O6)- Ba[Cu(1,3-pddadp)]8H2O (oktaedarska geometrija) su verifikovane rendgenskom strukturnom analizom. EPR spektralni rezultati su u skladu sa dobijenim geometrijama Ba[Cu(1,3-pd3ap)]6H2O i trans(O6)-Ba[Cu(1,3-pddadp)]8H2O kompleksa u vodenom rastvoru i čvrstom stanju, gde vrsta koordinovanja Cu(II) jona zavisi od broja šestočlanih helatnih prstenova i pH vrednosti. Utvrđen je uticaj kontra jona u slučaju bakar(II)-P-APK kompleksa zajedno sa ostalim strukturnim parametrima. Pokazano je da različiti katjoni mogu uticati na različito ponašanje obrazovanih kompleksa. DFT i TDDFT metode (B1LYP/6-311++G(d,p)) dale su dobre rezultate u izračunavanju i predviđanju UV-Vis spektara u slučaju bakar(II)-P-APK kompleksa. Molekulska mehanika ligandnog polja (LFMM) razvijena je za d9 bakar(II)-APK-komplekse. Radni set dobijen je DFT metodom za 14 kompleksa koji obuhvata E-APK i P-APK ligande N2O4 hromofore. DFT i LFMM metode predviđaju isti konformer najniže energije gde su strukture i energije konformera viših energija takođe u razumnom skladu...SUMMARY: The last few years aminopolycarboxylic chelates (APCs) have important application in metal detoxification, in treatment of infections, cardiovascular and neural diseases. Possession of six donor atoms gives them extraordinary chelation capacity to metal ions. Subject of this dissertation is synthesis of APC acids of ethanediamine (E-APC) and propanediamine (P-APC) type as well as their interaction with copper(II) and copper(I) ions. Characterization of the synthesized compounds was performed using various methods such as spectroscopy (UV-vis, IR), electron paramagnetic resonance (EPR), electrochemistry and computational chemistry. The structures of two complexes: Ba[Cu(1,3-pd3ap)]6H2O (trigonal-bipyramid geometry) and trans(O6)-Ba[Cu(1,3-pddadp)]8H2O (octahedral geometry) were verified by X-ray analysis. EPR spectral data are consistent with the obtained geometries of Ba[Cu(1,3-pd3ap)]6H2O and trans(O6)-Ba[Cu(1,3-pddadp)]8H2O complexes in solution and solid state, where type of Cu(II) ion coordination depends of number of six-membered chelate rings and pH value. The impact of counter-ions on the P-APC complexes is shown in detail together with the analysis of another strain parameters. It has been shown that different cations may affect the different behavior of formed complexes. On the basis of extensive DFT and TDDFT calculations the B1LYP/6- 311++G(d,p) level has been seen as an accurate theory for calculating and predicting the UV-Vis spectra in case of copper(II)-P-APC compounds. A ligand field molecular mechanics (LFMM) force field (FF) has been developed for d9 copper(II)-APC complexes. Training data were derived from density functional theory (DFT) geometry optimizations of 14 complexes comprising E-APC and P-APC ligands with N2O4 chromophore. DFT and LFMM methods predict the same lowest-energy conformer and the structures and energies of the higher-energy conformers are also in satisfactory agreement. The relative interaction energies computed by molecular mechanics (MM) correlate with the experimental logβ binding affinities. It has been shown that logβ decrease as the number of propionate arms increases favoring five-member chelate rings. Finally all previous claims served for the purpose of application in the treatment of neurotoxic disorders where E-APC and P-APC chelates were tested in in vitro and in vivo conditions (H41,2-pdta, H41,3-pdta, H4eddadp, H41,3-pddadp). Based on the results, two subgroups of chelates can be distinguished: (I) H41,2-pdta and H41,3-pdta ligands that clearly represent a complement chelating agents to commercial chelating drugs and (II) H4eddadp and S U M M A R Y H41,3-pddadp which demonstrate high copper selectivity. Theoretical experiments by molecular dynamics on systems which, apart from the tested APCs include well-known Hah1 copper transporter (in different conformational and structural forms) confirmed that affinity toward copper possess chelates with a mixed carboxylate rings. MMGBSA/MMPBSA+NMA results show that ΔG values of ligand-Hah1(dimer) follow H21,3-pddadp2-> H2eddadp-2> H21,2-pdta2-> H21,3-pdta2- descending order which is in accordance with the above mentioned affinity of APC ligands to copper(II) ion. Using the same computer methodology we showed that the toxicity of symmetrical chelate with mixed-rings can be caused by hydrogen bonds between chelates and particular amino-acid residues (Thr59) that lead to conformational changes of Lys60 responsible for initializing of copper transfer within cells. It is necessary to point out that future research of APCs application as chelating agents in medicine are still ahead, especially at the cellular and genetic levels. Results that underlying this doctoral thesis are introduction in mentioned issues