Kinetika i mehanizam supstitucionih reakcija kompleksa paladijuma(II) i rutenijuma(II)

Otkrićem antitumorskog dejstva cisplatine od strane B. Rozenberga 60-ih godina dvadesetog veka otpočela je prava revolucija u terapiji teških bolesti lekovima na bazi kompleksa jona prelaznih metala. Mnogobrojna istraživanja u ovoj oblasti dovela su do toga da se danas pored cisplatine i neki drugi kompleksi Pt(II), kao što su karboplatina i oksaliplatina, intezivno koriste u hemoterapiji. Poslednjih 40 godina veliki broj drugih kompleksa platine sintetisan je sa ciljem da se postigne bolja aktivnost u odnosu na cisplatinu. Pored kompleksa Pt(II) sa uobičajenom kvadratno-planarnom strukturom ispitivani su i tzv. neklasični kompleksi platine, gde spadaju kompleksi Pt(IV), polinuklearni Pt(II) kompleksi, ali i kompleksi drugih jona metala. Kompleksi Ru imaju veliki potencijal za upotrebu u terapiji kancera zbog svojih značajnih karakteristika, kao što su kinetika ligandne izmene, širok opseg oksidacionih stanja i sličnih osobina rutenijuma i gvožđe u biohemijskim procesima. Kinetika ligandne izmene određuje biološku aktivnost kompleksa metala i njegovu interakciju sa makromolekulima, kao što su proteini. Takođe su podjednako važne i interakcije sa amino kiselinama, peptidima i nukleotidima. Parametri kinetike ligandne izmene za komplekse Ru(II) i Ru(III) jona su slični parametrima za komplekse Pt(II) jona. Rutenijum u fiziološkim uslovima postoji u tri oksidaciona stanja: Ru(II), Ru(III) i Ru(IV), koja karakterišu različite biološke aktivnosti. Kompleksi Ru(III) su biološki inertniji od analognih Ru(II) i Ru(IV) kompleksa, a posebno je važno to što pod uticajem sredine mogu promeniti svoje oksidaciono stanje. Rutenijum se na molekularnom nivou ponaša kao gvožđe i može se vezati za albumin i transferin. Pošto ćelije kancera imaju povećanu potrebu za gvožđem, na njihovoj površini je povećan broj transferinskih receptora od 2 do 12 puta u odnosu na zdrave ćelije. Kompleksi Ru se tada vezuju za transferin i time selektivnije deluju na tumorska tkiva, pa su i sporedni neželjeni efekti smanjeni. Još jedna važna karakteristika kompleksa rutenijuma je sprečavanje odvajanja i migracije tumornih tkiva, kao i njihove adhezije na udaljenim mestima. Za ispitivanje kinetike i mehanizma supstitucionih reakcija kompleksa Pt(II) jedinjenja Pd(II) predstavljaju pogodne modele, uzimajući u obzir činjenicu da kompleksi Pd(II) reaguju 103-105 puta brže od analognih kompleksa Pt(II). Zbog jako velikog afiniteta prema sumpor- i azot-donorskim ligandima, kao i jako velike reaktivnosti, selektivnost kompleksa Pd(II) prema biomolekulima je mala, što ograničava upotrebu ovih jedinjenja kao antitumorskih agenasa. Međutim, poslednjih godina utvđeno je da neki kompleksi Pd(II) ipak poseduju antitumorsku aktivnost. U okviru ovog rada predstavljeni su rezultati dobijeni izučavanjem supstitucionih reakcija Ru(II) i Pd(II) kompleksa sa različitim sumpor- i azot- donorskim nukleofilima. Interakcije kompleksa jona prelaznih metala sa azot- i sumpor-donorskim biomolekulima su značajne, jer se pomoću njih objašnjava antikancerogena aktivnost kompleksa, ali i njihova toksičnost.Discovery of the antitumor activity of cisplatin by B. Rosenberg during the 60’s of the twentieth century started a real revolution in the treatment of severe disease drugs based on the transition metal ion complexes. Most of the results in this field have led to the conclusion that today, beside cisplatin, other complexes of Pt(II), such as carboplatin and oxaliplatin, are used extensively in chemotherapy. In the past 40 years a large number of other platinum complexes were synthesized in order to obtain a compound with better activity than cisplatin. In addition, the complexes of Pt(II) with conventional square-planar structure and so-called nonclassical platinum complexes, which include complexes of Pt(IV) and polynuclear Pt(II) complexes have been studied as well. However, the complexes of other metal ions were also included in these investigations. Ruthenium complexes have a great potential for application in cancer therapy because of their significant features, such as kinetics of ligand exchange, different oxidation states and property that ruthenium can mimic iron in biochemical processes. Kinetics of the ligand exchange determines their biological activity and interactions with macromolecules, such as proteins. The interactions with other biomolecules (amino acids, peptides and nucleotides) are also very important. The parameters of the ligand exchange kinetics for the Ru(II) and Ru(III) complexes are very similar to the values obtained for Pt(II) complexes. Under the physiological conditions ruthenium can exist in three oxidation states: Ru(II), Ru(III) and Ru(IV). Each of them has different biological acivity. Complexes of Ru(III) are biologically more inert than analogue Ru(II) or Ru(IV) complexes. Nevertheless, the ruthenium ion can easily change its oxidation state depending of the environment. Ruthenium can mimic iron and it may be bound to albumin and transferrin. Since cancer cells have an increased need for iron, on their surface accumulates increased number of transferrin receptors, 2 to 12 times more than in the case of healthy cells. Then, the ruthenium complexes bind to transferrin and thereby selectively act on tumor tissue, whereas side effects are reduced. Another important feature of the ruthenium complexes is preventing the separation and migration of tumor tissues and their adhesion on remote locations. For study of the kinetics and mechanism of the substitution reactions of Pt(II) complexes Pd(II) complexes are very suitable models, taking into account the fact that Pd(II) complexes react 103-105 times faster than the Pt(II) analogous. Due to the very high affinity for sulfur and nitrogen donor ligands, as well as a very high reactivity, the selectivity of Pd(II) complexes toward bio-molecules is small. All these facts limit the application of these compounds as antitumor agents. However, in recent years it was established that some complexes of Pd(II) possess antitumor activity. In this thesis are presented results obtained from the study of substitution reaction of some Ru(II) and Pd(II) complexes with different sulfur- and nitrogen-donor nucleophiles. The interactions of the complexes with sulfur- and nitrogen-containing bio-molecules are very important since that their antitumor activity as well as toxic side effects could be explained by these interactions