ABSTRACT
We report cytotoxic ruthenium(ii) complexes of the general formula [RuCl(cis-tach)(diphosphine)]+ (cis-tach = cis-cis-1,3,5-triaminocyclohexane) that have been characterised by 1H, 13C and 31P{1H} NMR spectroscopy, mass spectrometry, X-ray crystallography and elemental analysis. The kinetics of aquation and stability of the active species have been studied, showing that the chlorido ligand is substituted by water at 298 K with first order rate constants of 10-2-10-3 s-1, ideal for potential clinical use as anti-tumour agents. Strong interactions with biologically relevant duplex and quadruplex DNA models correlate with the activity observed with A549, A2780 and 293T cell lines, and the degree of activity was found to be sensitive to the chelating diphosphine ligand. A label-free ptychographic cell imaging technique recorded cell death processes over 4 days. The Ru(ii) cis-tach diphosphine complexes exhibit anti-proliferative effects, in some cases outperforming cisplatin and other cytotoxic ruthenium complexes.
Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Coordination Complexes/chemistry , Coordination Complexes/pharmacology , DNA/metabolism , Phosphines/chemistry , Ruthenium/chemistry , Antineoplastic Agents/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Coordination Complexes/metabolism , Humans , Kinetics , TemperatureABSTRACT
This chapter describes how de novo designed peptides can be used as novel preorganized ligands for metal ion coordination. The focus is on the design of peptides which are programmed to spontaneously self-assemble into α-helical coiled coils in aqueous solution, and how metal ion binding sites can be engineered onto and into these structures. In addition to describing the various design principles, some key examples are covered illustrating the success of this approach, including a more detailed example in the case study.
Subject(s)
Ions/chemistry , Metalloproteins/chemistry , Metals/chemistry , Peptides/chemistry , Amino Acid Sequence , Binding Sites/physiology , Ligands , Molecular Sequence Data , Protein Structure, SecondaryABSTRACT
Reaction of cis-[RuCl2(DMSO-S)3(DMSO-O)] with cis-1,3,5-triaminocyclohexane (tach) results in the formation of [RuCl(tach)(DMSO-S)2]Cl, a valuable precursor for a wide range of other tach-containing Ru complexes. Reaction of [RuCl(tach)(DMSO-S)2]Cl with the chelating nitrogen-based ligands (N-N = bipyridine, phenanthroline, and ethylenediamine) affords [Ru(N-N)(DMSO-S)2(tach)][Cl]2. A similar reaction between [RuCl(tach)(DMSO-S)]Cl with the chelating phosphorus-based ligands (P-P = dppm, dppe, dppp, dppb, dppv, and dppben) leads to the formation of [RuCl(P-P)(tach)]Cl. The structures of 10 examples of the tach-containing complexes have been determined by single crystal X-ray diffraction. An examination of the structural metrics obtained from these studies indicates that the tach ligand is a strong sigma donor. In addition, the presence of the NH2 groups in the tach ligand allow for participation in hydrogen bonding further modulating the coordinative properties of the ligand.
