New Heterodinuclear Metal Complexes as Anticancer Drug Candidates: the Advantages of Synergistic Effects from two Di1’ferent Transition Metal Centres
Progetto Combining two different pharmacologically active moieties in the same molecule
offers the opportunity to develop new compounds with improved efficacy. The goal of this project is the development of new heterobimetallic complexes and the assessment of their behaviour as anticancer agents. We selected oxaliplatin, auranofin and RAPTA-C as reference platinum, gold and ruthenium compounds, respectively, by virtue of their known anticancer activity and complementary biological targets. Therefore, synthetic strategies will be developed for the preparation of new Pt/Au, Pt/Ru and Au/Rn complexes combining the representative bioactive metal fragments (Pt(oxa1ate)(1,2-diaminocyc1ohexane)}, (Au(PEt3)}+ and (Ru(p-cymene)}2+. Thus, Pt(IV)-hydroxide precursors, derived from oxaliplatin, will be coupled with the (Au(PEt3)}+ fragment via a hydroxy- or carboxy-thiolate as linker, following established coupling reactions. Similarly, e-diimine ligands functionalized with a hydroxyl group will be used for the preparation of (Ru(II)(p-cymene)}2+ complexes and subsequently derivatized with the Pt(IV)-hydroxide precursor. Besides, e-diimine ligands featuring a pendant thiol group will be used to assemble novel Ru/Au complexes. The newly synthesized complexes will be studied for their solubility in water, stability in cell culture medium under physiological conditions and interaction with selected biomolecules by spectroscopic techniques and mass spectrometry.
Computational analyses will investigate the physieo-chemical properties of the heterobimetallic compounds and their possible fragmentation patterns in the physiological milieu and their binding to plausible sites of selected proteins.
The biological activity of the heterobimetallic compounds will be tested in different human colon and ovarian carcinoma cell lines using both classical monolayer culture and tridimensional spheroid culture. Additional cellular studies will be carried out to ascertain the metal uptake and subcellular localization of the heterobimetallic compounds or their fragments, the enhancement in Reactive Oxygen Species (ROS) levels, and the interaction with known biological targets such as DNA and Thioredoxin reductase (TrxR).