Sinteza, karakterizacija i ispitivanje mehanizma supstitucionih reakcija rutenijum(II) kompleksa

Abstract

Neorganska jedinjenja imaju važnu ulogu u biološkim i biomedicinskim procesima. Poznato je da mnoga jedinjenja koja se koriste u medicini nemaju samo organski način delovanja. Neki su aktivirani ili biotransformisani pomoću jona metala, uključujući metaloenzime. Drugi imaju direktan ili indirektan uticaj na metabolizam jona metala. Joni metala su takođe veoma važni za strukturu i funkciju nukleinskih kiselina. Pored toga, neesencijalni joni metala veoma često se koriste u biološkim sistemima u terapeutske i dijagnostičke svrhe. Nakon velikog uspeha cisplatine u lečenju kancera, posebna pažnja je posvećena razvoju rutenijum(II/III) kompleksa kao potencijalnih antitumorskih agenasa. Glavne razlike između rutenijuma i platine su: opseg dostupnih oksidacionih stanja, koordinacioni broj i geometrija. Vezivanje rutenijuma za biomolekule može biti reverzibilno, što može redukovati toksičnost metala, za razliku od platine. Rutenijum spada u VIII grupu prelaznih metala kao i gvožđe. Rutenijum može da zameni gvožđe pri vezivanju za biomolekule, a kako ćelije tumora imaju povećanu potrebu za gvožđem, to će omogućiti efikasniju dostavu kompleksa rutenijuma do željene mete. Primarni cilj razvoja rutenijum antitumorskih kompleksa je naći takvo jedinjenje koje će imati aktivnost prema tumorima koji su rezistentni na lekove platine. Sekundarni cilj je da aktivnost ne bi trebalo da bude praćena velikom toksičnošću, odnosno da jedinjenja imaju dobru podnošljivost i širok terapeutski opseg (tj. veliki opseg efektivne doze pre pojave štetnih efekata). Kako je DNK važna biološka meta za mnoge antitumorske komplekse različitih metala, od velikog je značaja poznavanje mehanizma koordinovanja za DNK potencijalnih antitumorskih agenasa. Utvrđeno je da se arena rutenijum(II) kompleksi koordinuju pretežno za guanin preko N7 azotovog atoma. Zatim su istraživanja okrenuta ka interakciji antitumorskih kompleksa rutenijuma sa proteinima. Nedavno je pronađeno da i enzimi mogu biti mete u hemoterapiji kancera.

Inorganic compounds play crucial roles in biological and biomedical processes, and it is evident that many organic compounds used in medicine do not have a purely organic mode of action; some are activated or biotransformed by metal ions including metalloenzymes, others have a direct or indirect effect on metal ion metabolism. Metal ions are also very important for the structure and function (in the case of RNA) of nucleic acids. Inorganic chemistry offers many opportunities for medicinal chemistry, and the discovery of metal-based drugs has moved on from chance discovery to rational drug design. Moreover, nonessential metal ions are very often used in biological systems either for therapeutic application or as diagnostic aids. After the great success of cisplatin in cancer treatment, special attention was devoted to evalaution of ruthenium complexes as potential antitumor agents. The major differences between ruthenium and platinum are the range of accessible oxidation states, coordination numbers and geometries available. Potentially, ruthenium binding to biomolecules may be reversible, in contrast to platinum, which subsequently reduces the toxicity of the metal. Ruthenium is in the same group of the periodic table as iron (group 8) and may mimic iron in its binding to biomolecules which, as tumor cells have a high demand for iron, would enable the drug to be delivered more effectively to the target side. The primary goal of developing ruthenium antitumor complexes is to find activity against tumors that are resistant to platinum drugs. A secondary goal is that activity should not be accompanied by severe toxicity, that the compounds have a good tolerability and a large therapeutic window (i.e. a large range of effective dosage before the onset of severe adverse effect). As DNA is an important potential biological target for many metal-based anticancer complexes, it is of a great importance to understand DNA binding properties of potential anticancer agents. It has been found that the arene ruthenium(II) ethylenediamine complexes bind preferentially to guanine residues in double-helical DNA. Currently drug development involving ruthenium complexes has shifted from DNA targeting toward protein targeting drugs. Recently, it was found that enzymes also can be targets in cancer chemotherapy.