Photoactive and luminescent transition metal complexes as anticancer agents : a guiding light in the search for new and improved cancer treatments

Cancer continues to be responsible for the deaths of more than 9 million people worldwide each year. Current treatment options are diverse, but low success rates, particularly for those with late-stage cancers, continue to be a problem for clinicians and their patients. The effort by researchers globally to find alternative treatment options is ongoing. In the present study, we focused on innovations in inorganic anticancer therapies, specifically those with photoactive and luminescent properties. Transition metals offer distinct advantages compared to wholly organic compounds in both chemotherapeutics and luminescence properties. Here we report on the characteristics that result from discrete structural changes that have been expertly used to fine-tune their properties, and how diverse inherent luminescent properties have been widely employed to monitor cellular localization to photodynamic therapy

DNA as a target for antimicrobials

Resistance to antimicrobials is one of the biggest threats to our healthcare. However, in the last few decades very few truly novel antimicrobial compounds have been brought to market, creating the potential threat of a post-antibiotic era in which infections are very difficult to treat. Identification of novel compounds with antimicrobial activity is therefore paramount. Ideally, novel compounds should be designed that are active against targets that are not or barely used, as it is less likely that resistance already exists against such compounds. One example of an underexplored target in the treatment of infections is DNA. In this review we describe a number of DNA binding compounds and discuss potential opportunities and problems

An accurate spline polynomial cubature formula for double integration with logarithmic singularity

The paper studied the integration of logarithmic singularity problem J(ӯ) = ∫∫Δζ(ӯ)log|ӯ - ӯ 0∗|dA, where ӯ=(α,β), y0=(α0,β0) the domain Δ is rectangle Δ = [r1, r2] × [r3, r4], the arbitrary point ӯ ϵ Δ and the fixed point ӯ0 ϵ Δ. The given density function ζ(ӯ), is smooth on the rectangular domain Δ and is in the functions class C2,τ (Δ). Cubature formula (CF) for double integration with logarithmic singularities (LS) on a rectangle Δ is constructed by applying type (0, 2) modified spline function DΓ(P). The results obtained by testing the density functions ζ(ӯ) as linear and absolute value functions shows that the constructed CF is highly accurate

Combining the platinum(ii) drug candidate kiteplatin with 1,10-phenanthroline analogues

Platinum complexes of the type [Pt(PL)(AL)]2+ where PL is a derivative of 1,10-phenanthroline and AL is cis-1,4-diaminocyclohexane (1,4-dach), have been synthesised and characterised by ultraviolet spectroscopy, elemental microanalysis, nuclear magnetic resonance and X-ray crystallography. The calf-thymus DNA binding affinity of these complexes was determined by isothermal titration calorimetry, revealing higher DNA affinity than their 1S,2S-diaminocyclohexane analogues. In vitro cytotoxicity was assessed in eleven human cell lines, revealing unexpectedly low activity for the 1,4-dach complexes

Cyclooxygenase-inhibiting platinum(IV) prodrugs with potent anticancer activity

Platinum(IV) prodrugs of the [Pt(PL)(AL)(COXi)(OH)]2+ type scaffold (where PL is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, AL is 1S,2S-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, 4, exhibited a GI50 of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that 1 and 2 inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs 1–4 was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity

Synthesis and analysis of the anticancer activity of platinum(ii) complexes incorporating dipyridoquinoxaline variants

Eight platinum(ii) complexes with anticancer potential have been synthesised and characterised. These complexes are of the type [Pt(I)(A)], where I is either dipyrido[3,2-f:2′,3′-h]quinoxaline (dpq) or 2,3-dimethyl-dpq (23Medpq) and A is one of the R,R or S,S isomers of either 1,2-diaminocyclohexane (SS-dach or RR-dach) or 1,2-diaminocyclopentane (SS-dacp or RR-dacp). The CT-DNA binding of these complexes and a series of other complexes were assessed using fluorescent intercalator displacement assays, resulting in unexpected trends in DNA binding affinity. The cytotoxicity of the eight synthesised compounds was determined in the L1210 cell line; the most cytotoxic of these were [Pt(dpq)(SS-dach)]Cl and [Pt(dpq)(RR-dach)]Cl, with IC values of 0.19 and 0.80 μM, respectively. The X-ray crystal structure of the complex [Pt(dpq)(SS-dach)](ClO)·1.75HO is also reported. This journal i

Self-assembly of an imidazolate-bridged FeIII/CuII heterometallic cage

A rare, discrete, mixed-valent, heterometallic Fe(III)/Cu(II) cage, [CuFeL](ClO)χ solvent (HL = tris{[2-{(imidazole-4-yl)methylidene}amino]ethyl} amine), was designed and synthesized via metal-ion-directed self-assembly with neutral tripodal metalloligands. The formation of this coordination cage was demonstrated by X-ray crystallography, ESI mass spectrometry, FT-IR, and UV-vis-NIR spectroscopy

Metallo-helical complexes resolutely pure helices

Helical coordination compounds that show promising antibiotic activity in aqueous media have been assembled directly in their optically pure form, without the need for a resolution step

Synthesis of flexible bis-intercalating ruthenium (II) complexes

We report the synthesis, resolution and characterisation of a number of novel ruthenium(II) complexes. Four mononuclear complexes, [Ru(dpq)2(3-Br-phen)]2+, [Ru(dpq)2(4-Cl-phen)]2+, [Ru(dpq)2(5-Cl-phen)]2+ and [Ru(dpq)2(phen)]2+ were synthesised (dpq = dipyrido[3,2-d:2,3-f]quinoxaline, phen = 1,10-phenanthroline, 3-Br-phen = 3-bromo-1,10-phenanthroline, 4-Cl-phen = 4-chloro-1,10-phenanthroline, 5-Cl-phen = 5-chloro-1,10-phenanthroline). These complexes were resolved using the chiral TRISPHAT anion, [tris(tetrachlorocatecholato)phosphate(V)]-. Racemic mononuclear complexes were used in the synthesis of the racemic dinuclear complexes, [{Ru(dpq)2}2-(phen-n-SOS-n-phen)]4+ (SOS = 2-mercaptoethyl ether, n = 3, 4 or 5). Resolved mononuclear complexes were used to synthesise stereoselectively the - and -enantiomers of their respective dinuclear complexes. All metal complexes were characterised by 1H NMR, ESI-MS, UV/Vis and luminescence spectroscopy. Resolved metal complexes were further characterised using CD spectroscopy and chiral 1H NMR titrations

Evidence for chiral discrimination of ruthenium(II) polypyridyl complexes by DNA

Here we report on the synthesis and enantiomeric resolution of metal complexes of the type [Ru(bpyMe₂)₂L]₂_ (where bpyMe₂ = 4,4_-dimethyl-2,2_-bipyridine and L = 1,10-phenanthroline (phen), dipyrido[3,2-a:2_3_-c]- quinoxaline (dpq), dipyrido[3,2-a:2_3_-c](6,7,8,9-tetrahydro)phenazine (dpqc) or dipyrido[3,2-a:2_3_-c]phenazine (dppz)). DNA-paper chromatography, absorption spectroscopy, gel electrophoresis and viscometry of linear DNA were used to assess the association and affinity for DNA of the forementioned complexes. Optical resolution of the complexes was achieved by solvent recycled chromatography using Sephadex cation exchange resin and disodium (_)-O,O_-dibenzoyl-L-tartrate. Paper chromatography successfully elucidated the relative binding affinities of the metal complexes investigated in the following order phen (0.68) < dpq (0.36) < dpqc (0.14) < dppz (0.09). Absorption spectroscopy experiments indicated that each of the complexes were in close association with the DNA. Electrophoresis of the plasmid DNA incubated with the Δ complexes of dppz or dpqc show unwinding. The Λ-isomer of dppz resulted in smearing due to less effective binding whereas the Λ-isomer of dpqc showed no unwinding at all. Unexpectedly, rac-Ru(bpyMe₂)₂(dpq)]₂_ showed greater unwinding than either isomer. DNA-viscosity experiments provided evidence that both the Δ and Λ-isomers of dppz and dpqc bind by intercalation. However, Δ and Λ-[Ru(bpyMe₂)₂(dpq)]₂_ bind through different modes, the Δ isomer by intercalation and the Λ isomer by partial intercalation. The conclusions that can be drawn from this is that the extended methyl groups in the 4- and 4_-positions on the bpyMe₂ ligand are critical in eliciting different enantiomeric interactions with the walls of the DNA grooves