Guy James Clarkson

An integrated multimodal imaging workflow of cryogenic super-resolution fluorescence microscopy and soft X-ray tomography, Orbitrap secondary ion mass spectrometry, and inductively coupled plasma-mass spectrometry has revealed the unexpected targeting of a half-sandwich cyclopentadienyl Rh(III) phenylazopyridine anticancer complex to cellular lipid membranes and lipid droplets. The complex accumulates in plasma membranes with a surprisingly intense switch-on luminescence in living cancer cells, drives remodeling of lipid droplet architecture, and penetrates deeply into lipid-rich tissue environments. DFT modeling shows strong supramolecular interactions between the complex and glycerophosphorylcholine lipids.

Classical structure-activity relationships for square-planar Pt(II) anticancer complexes were based on the activity of cis-[PtCl₂(NH₃)₂] (cisplatin) and inactivity of the trans isomer. Many other families of cis-diamine complexes and analogous octahedral Pt(IV) prodrugs are active. Here, we report the chemical and biological activities of isomeric photoactivatable cis,trans,cis- and all-trans-[Pt(N₃)₂(OH)₂(MNZ)₂] complexes (MNZ = metronidazole, 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole). While both are relatively nontoxic in the ground state, only the all-trans isomer is cytotoxic toward bladder cancer cells on excitation with visible light and under hypoxia. Studies of DNA interstrand cross-links and photocytotoxicity toward wild-type and nucleotide-excision-repair deficient cells suggest that, unlike cisplatin, DNA is not the major target site of these isomers. Differences in photoactivation pathways were also explored using time-dependent DFT calculations. The key differences between the isomers on irradiation are the more rapid photoactivation of the all-trans complex, generation of azidyl radicals, retention of its metronidazole ligands, higher accumulation in cancer cells, binding to DNA, RNA, and proteins, and induction of apoptosis and mitochondrial membrane damages. These findings provide a basis for the design of future photochemotherapeutic platinum anticancer prodrugs.

We report the synthesis and characterization of ten novel half‐sandwich Rh(III) azopyridine complexes as potential anticancer agents, with the general formula [(η⁵‐Cp^x)Rh(4‐R₂‐phenylazopy‐5‐R₁)Cl]PF₆, where Cp^x = Cp*, Cp^xPh or Cp^xPhPh, R₁ = H, Br, or CF₃, and R₂ = H, OH or NMe₂. X‐ray crystallographic data for complex 2 (R₁ = Br, R₂ = OH, Cp^x = Cp^xPh) and complex 3 (R₁ = CF₃, R₂ = OH, Cp^x = Cp^xPh) confirm their typical half‐sandwich “piano‐stool” geometry. The substituents have a major influence on the cytotoxicity of these complexes toward human ovarian (A2780 and cisplatin‐resistant A2780cis), lung (A549) and prostate (PC‐3) cancer cells, and non‐cancerous human lung fibroblasts (MRC‐5). Potencies range from sub‐micromolar to inactive (>50 µM). They were non‐cross‐resistant with cisplatin, and complex 9 (R₁ = H, R₂ = NMe₂, Cp^x = Cp^*) showed some selectivity (>3x) for A549 cancer cells versus normal cells. The highly active, lipophilic complex 2 was strongly accumulated by cells and catalyzed the oxidation of NADH (reduced nicotinamide adenine dinucleotide) to NAD⁺, and GSH (glutathione) to GSSG. Notably, complex 2 is almost an order of magnitude less toxic toward zebrafish in vivo than cisplatin, despite being 10‐fold more active in A549 cells. These studies demonstrate how the chemical and biological activities of this series of half‐sandwich organorhodium(III) complexes can be finely tuned by the choice of substituents on the cyclopentadienyl and azopyridine ligands. The complexes appear to have an unusual mechanism of anticancer activity, associated not only with Rh(III) but also with the phenylazopyridine, cyclopentadienyl, and the chlorido ligands.

In the formation of calcium–organic frameworks with a tetracarboxylate ligand the solvent choice influences the connectivity of the metal centres.

The photochemotherapeutic activity of diazido Pt(iv) complexes towards bladder cancer, a common cancer with expensive treatment, has been tuned via modification of trans N-heterocyclic ligands, to give a candidate for preclinical development.

DFT calculations on a conjugate of ferrocene to an octahedral Pt(iv) complex reveal Fe-to-Pt charge transfer, promoting longer-wavelength photoactivation, enhanced cellular accumulation, potent anticancer activity, and cell death via ferroptosis.

On the basis of steric hindrance, one carbonyl group in a diketone can be reduced in a regioselective manner, with high enantioselectivity. The methodology can be extended to ketones with varied length of hydrocarbon chain spacing, and the products can be converted by oxidation to hydroxy esters or lactones without loss of enantiopurity.

Biphenyl-fused-dioxacyclodecynes are a promising class of strained alkyne for use in Cu-free ‘click’ reactions.

In this study, we report the synthesis and characterization of some heteroleptic Cr(III) complexes of the form [Cr(Phen)₂L](OTf)₃, where Phen = 1,10-phenanthroline and L is either 2,2'-bipyridine (bpy) or its derivatives, such as 4,4'-dimethyl-2,2'-bipyridine (4,4'-DMB), 4,4'-dimethoxy-2,2'-bipyridine (4,4'-DMOB), 4,4'-ditert-butyl-2,2'-bipyridine (4,4'-d^tbpy), 5,5'-dimethyl-2,2'-bipyridine (5,5'-DMB), 4,4'-dimethoxycarbonyl-2,2'-bipyridine (4,4'-dmcbpy) or 1,10-phenanthroline derivatives, such as 5-methyl-1,10-phenanthroline (5-Me-Phen) and 4,7-dimethyl-1,10-phenanthroline (4,7-DMP). Heteroleptic complexes were prepared in two stages via the intermediate [Cr(Phen)₂(CF₃SO₃)₂](CF₃SO₃) and five examples have been crystallographically characterized. Steady-state absorption and luminescence emission characteristics of these complexes were measured in 1 M HCl solutions. The luminescence quantum yield of these complexes was found to be the lowest for [Cr(Phen)₂(4,4'-dmcbpy)](OTf)₃ and the highest for [Cr(Phen)₂(4,4'-DMB)](OTf)₃ with values of 0.31 × 10^-2 and 1.48 × 10^-2, respectively. The calculated excited state energy, E_0-0, was found to vary within the narrow range of 163.1-165.0 kJ mol^-1 across the series. Transient absorption spectra in degassed, air-equilibrated, and oxygen-saturated 1 M HCl aqueous solutions were also measured at different time decays and demonstrated no significant differences, indicating the absence of any ion-separated species in the excited state. Excited-state decay traces at the wavelength of maximum absorption were used to calculate oxygen quenching rate constants, k_q, which were found to be in the range 3.26-5.27 × 10⁷ M^-1 s^-1. Singlet oxygen luminescence photosensitized by these complexes was observed in D₂O, and its luminescence intensity at 1270 nm was used for the determination of singlet oxygen quantum yields for these complexes, which were in the range of 0.20-0.44, while the fraction of the excited ²E state quenched by oxygen was in the range of 0.22-0.68, and the efficiency of singlet oxygen production was in the range of 0.44-0.90. The mechanism by which the excited ²E state is quenched by oxygen is explained by a spin statistical model that predicts the balance between charge transfer and noncharge transfer deactivation pathways, which was represented by the parameter p_CT that was found to vary from 0.35 to 0.68 for this series of Cr(III) complexes.