Ruthenium(ii) and palladium(ii) homo- and heterobimetallic complexes: synthesis, crystal structures, theoretical calculations and biological studies

摘要

Four Ru-Pd heterobimetallic complexes, each one in two different coordination modes (NNSS and NS) having metals connected by a binucleating dialkyldithiooxamidate [N(R)SC-CS(R)N] [R = methyl, ethyl, n-butyl and isopropyl], were prepared by reacting the monochelate [(tri(n)propyl-phosphine)ClPd(HR2C2N2S2 kappa-S,S-Pd)] with [(eta(6)-p-cymene)RuCl2](2). Furthermore, two palladium homobimetallic complexes having two (tri(n)propyl-phosphine)ClPd moieties joined by a diethyldithiooxamidate in both kappa-N,S Pd, kappa-N ',S ' Pd ' and kappa-N,N ' Pd, kappa-S,S ' Pd ' coordination modes were synthesized. For both kinds of complexes, homo- and heterobimetallic, at room temperature and in chloroform solution, the NNSS coordination mode (kinetic compounds) turns out to be unstable and therefore the resulting complexes rearrange into a thermodynamically more stable form (NS coordination mode). The crystal structures of [(tri(n)propyl-phosphine)ClPd](2)[mu-(ethyl)(2)-DTO kappa-N,S Pd, kappa-N ',S ' Pd '] (2) and [(eta(6)-p-cymene)ClRu][mu-(methyl)(2)-DTO kappa-N,S Ru, kappa-N,S Pd] [(tri(n)propyl-phosphine)ClPd] (1c) were determined by solid state X-ray crystallography. Moreover, the higher stability of the thermodynamic species in the heterobimetallic complexes (Ru-Pd) was evaluated by means of computational studies in accordance with the maximum hardness principle. All stable NS complexes (i.e.1c-4c, 2 and the previously reported homobimetallic Ru complex 3) were tested against two leukemia cell lines, namely the drug-sensitive CCRF-CEM cell line and its multidrug-resistant sub-cell line CEM/ADR5000 showing anti-proliferative activity in the low micromolar range (similar to 1-5 mu M) and micromolar range (similar to 10-25 mu M), respectively. In addition, these complexes efficaciously block at least two out of the three proteolytic activities of the tumor target 20S proteasome, with heterobimetallic complex 3c and homobimetallic complex 3 possessing the best inhibitory profil