Multi-target heteroleptic palladium bisphosphonate complexes

CIPRIANI, MICAELLA; ROSTÁN, SANTIAGO; LEÓN, IGNACIO; LI, ZHU-HONG; GANCHEFF, JORGE S.; KEMMERLING, ULRIKE; OLEA AZAR, CLAUDIO; ETCHEVERRY, SUSANA; DOCAMPO, ROBERTO; GAMBINO, DINORAH; OTERO, LUCÍA

JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY

SPRINGER

Lugar: Berlin; Año: 2020 vol. 25 p. 509 - 519

0949-8257

Bisphosphonates are the most commonly prescribed drugs for the treatment of osteoporosis and other bone illnesses. Someof them have also shown antiparasitic activity. In search of improving the pharmacological profile of commercial bisphosphonates,our group had previously developed first row transition metal complexes with N-containing bisphosphonates(NBPs). In this work, we extended our studies to heteroleptic palladium?NBP complexes including DNA intercalatingpolypyridyl co-ligands (NN) with the aim of obtaining potential multi-target species. Complexes of the formula[Pd(NBP)2(NN)]·2NaCl·xH2O with NBP = alendronate (ale) or pamidronate (pam) and NN = 1,10 phenanthroline (phen) or2,2′-bipyridine (bpy) were synthesized and fully characterized. All the obtained compounds were much more active in vitroagainst T. cruzi (amastigote form) than the corresponding NBP ligands. In addition, complexes were nontoxic to mammaliancells up to 50?100 μM. Compounds with phen as ligand were 15 times more active than their bpy analogous. Related to thepotential mechanism of action, all complexes were potent inhibitors of two parasitic enzymes of the isoprenoid biosyntheticpathway. No correlation between the anti-T. cruzi activity and the enzymatic inhibition results was observed. On the contrary,the high antiparasitic activity of phen-containing complexes could be related to their ability to interact with DNA inan intercalative-like mode. These rationally designed compounds are good candidates for further studies and good leadersfor future drug developments.