Metal complexes are increasingly being used to inhibit enzymes. The reasons for this increased interest arise from the special features that metal complexes offer, e.g. the facile construction of 3D architectures that tightly fill enzyme active sites increasing selectivity and the possibility of facile coordination to protein residues that enhances enzyme inhibition. In this review we classify the main modes of enzyme inhibition by metal-based complexes and correlate the enzyme inhibition activity to macroscopic properties such as anticancer activity.
Novel gold(I) "click" carbene(1,2,3-triazolylidene) complexes have been synthesised, characterised and exploited for the self-assembly of a metallomacrocycle and as precatalysts for gold(I)-catalysed reactions.
The Cu(I)-catalyzed 1,3-cycloaddition of organic azides with terminal alkynes, the CuAAC "click" reaction is currently receiving considerable attention as a mild, modular method for the generation of functionalized ligand scaffolds. Herein we show that mild one-pot "click" methods can be used to readily and rapidly synthesize a family of functionalized bidentate 2-pyridyl-1,2,3-triazole ligands, containing electrochemically, photochemically, and biologically active functional groups in good to excellent yields (47-94%). The new ligands have been fully characterized by elemental analysis, HR-ESI-MS, IR, (1)H and (13)C NMR and in three cases by X-ray crystallography. Furthermore we have demonstrated that this family of functionalized "click" ligands readily form bis-bidentate Pd(II) complexes. Solution studies, X-ray crystallography, and density functional theory (DFT) calculations indicate that the Pd(II) complexes formed with the 2-(1-R-1H-1,2,3-triazol-4-yl)pyridine series of ligands are more stable than those formed with the [4-R-1H-1,2,3-triazol-1-yl)methyl]pyridine "click" ligands.
Ruthenium(II) arene compounds have been modified with
the naphthalimide group, tethered via the arene ligand, i.e. {dichloro[η6-N-(phenylalkyl)(4-dimethylamino)-1,8-naphthalimide](pta)ruthenium(II)}
(alkyl = methyl, ethyl, propyl, pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane),
or via an imidazole group, i.e. {dichloro(η6-arene)(N-[3-(imidazol-1-yl)propyl]-1,8-naphthalimide)ruthenium(II)}
(arene = p-cymene, toluene). All the compounds are
reasonably cytotoxic (ca. 2–49 μM) toward cancer cells,
and the arene-linked compounds also display selectivity in that they
are less cytotoxic toward model healthy cells. Mechanistic studies
show that the ruthenium center does not readily react with DNA but
preferentially binds to proteins. In contrast, the naphthalimide group
is a strong DNA intercalator, and combined, the complexes might be
expected to simultaneously cross-link DNA and proteins.
Taking advantage of the facile and versatile synthetic properties of 'click' 1,2,3-triazolylidene N-heterocyclic carbenes (tzNHC's), a range of new organometallic Ru(II) and Os(II) arene complexes containing functionalised tzNHC ligands, [M(η(6)-p-cymene)(tzNHC)Cl2] [M = Ru(II), Os(II)], have been synthesised and fully characterised, including the X-ray crystal structure of one of the Os(II) complexes. The tzNHC ligands remain coordinated to the metal centres under relevant physiological conditions, and following binding to the model protein, ubiquitin. The in vitro cytotoxicity of the compounds towards human ovarian cancer cells is dependent on the substituent on the tzNHC ligand but is generally <50 μM and in some cases <1 μM, whilst still retaining a high degree of selectivity towards cancer cells over healthy cells (1.85 μM in A2780 ovarian cancer cells versus 435 μM in human embryonic kidney cells in one case).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.