Homo- and heteroleptic metal complexes of bisphosphonates targeting enzymes of the isoprenoid biosynthetic pathway and/or DNA

CIPRIANI M.; DEMORO B; LEÓN IE; ZHU-HONG LIC; GALIZZI M.; MALAYIL L; ETCHEVERRY S B; DOCAMPO R.; GAMBINO D; OTERO L.

Wrocław

Simposio; International Symposium on Metal Complexes (ISMEC 2015); 2015

Bisphosphonates (BPs) are the most commonly prescribed drugs for the treatment of osteoporosis and other bone illnesses. In addition, some of these drugs have also shown antitumoral and antiparasitic activity [1]. In the search of improving the pharmacological profile of commercial bisphosphonates our group has developed first row transition metal complexes of risedronate, alendronate and pamidronate. Obtained complexes were more active in vitro against Trypanosoma cruzi, ethiological agent of Chagas disease, than the free BPs and they resulted selective inhibitors of the parasitic enzyme farnesyl diphosphate synthase (TcFPPS) [2]. Based on these promising results, we extended our studies to the bisphosphonate ibandronate (IBA) and developed heteroleptic palladium complexes including phenanthroline or bipyridine as co-ligands. Complexes of the formula [MII(IBA)(H2O)4]Cl, with M = Co, Mn, Ni and [Pd(BP)2(N-N)]2NaCl with BP = alendronate or pamidronate and N-N = phenanthroline or bipyridine were synthesized and fully characterized. All obtained complexes were evaluated in vitro against amastigote form of T. cruzi resulting much more active than the corresponding BP ligands and being non toxic to mammalian cells up to 50-100 µM. Complexes were inhibitors of TcFPPS and in particular, IBA complexes did not inhibit human FPPS presenting a selective antiparasitic activity. In addition, all complexes resulted good inhibitors of another parasitic enzyme of the isoprenoid biosynthetic pathway: solanesyl-diphosphate synthase (TcSPPS). For the palladium mixed-ligand species including DNA intercalating compounds as co-ligands, human FPPS inhibitory effect was also observed. Therefore, biological activity against tumor cell lines (human lung adenocarcinoma A549 and human osteosarcoma MG-63) was also studied. Phenanthroline compounds were the most active palladium complexes both in tumors and in parasites. Based on these results, we propose that the mechanism of action of the mixed ligand species could be related to DNA-binding mediated by the intercalating ligands. In these sense, interaction of these complexes with calf thymus DNA was studied through fluorescence experiments using ethidium bromide as competitive intercalating agent. In fact, a strong quenching on the fluorescence of DNA-EB adduct was observed for both complexes containing phenanthroline as ligand while no effect of the bipyridine ones was detected. These rationally designed compounds are goods candidates for further studies and good leaders for future developments.