Gold(I) metallocyclophosphazenes with antibacterial potency and antitumor efficacy. Synergistic antibacterial action of a heterometallic gold and silver-cyclophosphazene

One of the most important uses of phosphazenes today involves its biomedical applications. They can also be employed as scaffolds for the design and construction of a variety of ligands in order to coordinate them to metallic drugs. The coordination chemistry of the (amino)cyclotriphosphazene ligand, [N3P3(NHCy)(6)], towards gold(I) complexes has been studied. Neutral complexes, [N3P3(NHCy)(6){AuX}(n)] (X = Cl or C6F5; n = 1 or 2) (1-4), cationic complexes, [N3P3(NHCy)(6){Au(PR3)}(n)](NO3)(n) (PR3 = PPh3, PPh2Me, TPA; n = 1, 2 or 3) (6-12) [TPA = 1,3,5-triaza-7-phosphaadamantane] and a heterometallic compound [N3P3(NHCy)(6){Au(PPh3)}(2){Ag(PPh3)}](NO3)(3) (13) have been obtained and characterized by various methods including single-crystal X-ray diffraction for 7, which confirms the coordination of gold atoms to the nitrogens of the phosphazene ring. Compounds 1, 4, 6-13 were screened for in vitro cytotoxic activity against two tumor human cell lines, MCF7 (breast adenocarcinoma) and HepG2 (hepatocellular carcinoma), and for antimicrobial activity against five bacterial species including Gram-positive, Gram-negative, and Mycobacteria. Both the median inhibitory concentration (IC50) and minimum inhibitory concentration (MIC) values are among the lowest found for any gold or silver derivatives against the cell lines and particularly against the Gram-positive (S. aureus) strain and the mycobacteria used in this work. Structure-activity relationships are discussed in order to determine the influence of ancillary ligands and the number and type of metal atoms (silver or gold). Compounds 4 and 8 showed not only maximal potency on human cells but also some tumour selectivity. Remarkably, compound 13, with both gold and silver atoms, showed outstanding activity against both Gram-positive and Gram-negative strains (nanomolar range), thus having a cooperative effect between gold and silver, with MIC values which are similar or lower than those of gentamicine, ciprofloxacin and rifampicine. The broad spectrum antimicrobial efficacy of all these metallophosphazenes and particularly of heterometallic compound 13 could be very useful to obtain materials for surfaces with antimicrobial properties that are increasingly in demand.

Automated summary

Phosphazenes have important biomedical applications, as they can be used as scaffolds for ligand design and construction for coordination with metallic drugs. This study investigated the coordination chemistry of the phosphazene ligand [N3P3(NHCy)(6)] with gold(I) complexes. Various neutral and cationic complexes were synthesized and characterized, and their cytotoxic and antimicrobial activities were evaluated. The heterometallic compound 13 showed outstanding antimicrobial efficacy. These findings are significant for the design of materials with antimicrobial properties.