Publications by authors named "Peter J Sadler"

311 Publications

Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

Dalton Trans 2021 Jul 19. Epub 2021 Jul 19.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK. and Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Complexes trans,trans,trans-[Pt(N3)2(OH)(OCOR)(py)2] where py = pyridine and where OCOR = succinate (1); 4-oxo-4-propoxybutanoate (2) and N-methylisatoate (3) have been synthesized by derivation of trans,trans,trans-[Pt(OH)2(N3)2(py)2] (4) and characterised by NMR and EPR spectroscopy, ESI-MS and X-ray crystallography. Irradiation of 1-3 with green (517 nm) light initiated photoreduction to Pt(ii) and release of the axial ligands at a 3-fold faster rate than for 4. TD-DFT calculations showed dissociative transitions at longer wavelengths for 1 compared to 4. Complexes 1 and 2 showed greater photocytotoxicity than 4 when irradiated with 420 nm light (A2780 cell line IC50 values: 2.7 and 3.7 μM) and complex 2 was particularly active towards the cisplatin-resistant cell line A2780cis (IC50 3.7 μM). Unlike 4, complexes 1-3 were phototoxic under green light irradiation (517 nm), with minimal toxicity in the dark. A pKa(H2O) of 5.13 for the free carboxylate group was determined for 1, corresponding to an overall negative charge during biological experiments, which crucially, did not appear to impede cellular accumulation and photocytotoxicity.
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http://dx.doi.org/10.1039/d1dt01730fDOI Listing
July 2021

Facile protein conjugation of platinum for light-activated cytotoxic payload release.

Chem Commun (Camb) 2021 Jul 12. Epub 2021 Jul 12.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK.

The novel Pt(iv) complex trans,trans-[Pt(N3)2(Py)2(OH)(OCO-(PEG)2-NHCSNH-Ph-NCS)] (Pt4) conjugates to the side chain of lysine amino acids in proteins under mild conditions. Reaction with myoglobin generated a bioconjugate that was stable in the dark, but released a Pt(iv) prodrug upon visible light irradiation. A similar procedure was used to conjugate Pt4 to the antibody trastuzumab, resulting in the first photoactivatable Pt(iv)-antibody conjugate, demonstrating potential for highly selective cancer phototherapy.
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http://dx.doi.org/10.1039/d1cc02722kDOI Listing
July 2021

Metallodrugs are unique: opportunities and challenges of discovery and development.

Chem Sci 2020 Nov 12;11(48):12888-12917. Epub 2020 Nov 12.

Department of Chemistry, University of Warwick Gibbet Hill Road Coventry CV4 7AL UK

Metals play vital roles in nutrients and medicines and provide chemical functionalities that are not accessible to purely organic compounds. At least 10 metals are essential for human life and about 46 other non-essential metals (including radionuclides) are also used in drug therapies and diagnostic agents. These include platinum drugs (in 50% of cancer chemotherapies), lithium (bipolar disorders), silver (antimicrobials), and bismuth (broad-spectrum antibiotics). While the quest for novel and better drugs is now as urgent as ever, drug discovery and development pipelines established for organic drugs and based on target identification and high-throughput screening of compound libraries are less effective when applied to metallodrugs. Metallodrugs are often prodrugs which undergo activation by ligand substitution or redox reactions, and are multi-targeting, all of which need to be considered when establishing structure-activity relationships. We focus on early-stage drug discovery, highlighting the challenges of evaluating anticancer, antimicrobial and antiviral metallo-pharmacophores in cultured cells, and identifying their targets. We highlight advances in the application of metal-specific techniques that can assist the preclinical development, including synchrotron X-ray spectro(micro)scopy, luminescence, and mass spectrometry-based methods, combined with proteomic and genomic (metallomic) approaches. A deeper understanding of the behavior of metals and metallodrugs in biological systems is not only key to the design of novel agents with unique mechanisms of action, but also to new understanding of clinically-established drugs.
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http://dx.doi.org/10.1039/d0sc04082gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163330PMC
November 2020

Biogenic metallic elements in the human brain?

Sci Adv 2021 Jun 9;7(24). Epub 2021 Jun 9.

School of Pharmacy and Bioengineering, Guy Hilton Research Centre, Thornburrow Drive, Keele University, Staffordshire ST4 7QB, UK.

The chemistry of copper and iron plays a critical role in normal brain function. A variety of enzymes and proteins containing positively charged Cu, Cu, Fe, and Fe control key processes, catalyzing oxidative metabolism and neurotransmitter and neuropeptide production. Here, we report the discovery of elemental (zero-oxidation state) metallic Cu accompanying ferromagnetic elemental Fe in the human brain. These nanoscale biometal deposits were identified within amyloid plaque cores isolated from Alzheimer's disease subjects, using synchrotron x-ray spectromicroscopy. The surfaces of nanodeposits of metallic copper and iron are highly reactive, with distinctly different chemical and magnetic properties from their predominant oxide counterparts. The discovery of metals in their elemental form in the brain raises new questions regarding their generation and their role in neurochemistry, neurobiology, and the etiology of neurodegenerative disease.
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http://dx.doi.org/10.1126/sciadv.abf6707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189590PMC
June 2021

Ligand-centred redox activation of inert organoiridium anticancer catalysts.

Chem Sci 2020 May 15;11(21):5466-5480. Epub 2020 May 15.

Department of Chemistry, University of Warwick Coventry CV4 7AL UK

Organometallic complexes with novel activation mechanisms are attractive anticancer drug candidates. Here, we show that half-sandwich iodido cyclopentadienyl iridium(iii) azopyridine complexes exhibit potent antiproliferative activity towards cancer cells, in most cases more potent than cisplatin. Despite their inertness towards aquation, these iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes, and liberate reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS attack on the azo bond facilitates the substitution of iodide by GS, and leads to formation of GSSG and superoxide if O is present as an electron-acceptor, in a largely exergonic pathway. Reactions of these iodido complexes with GSH generate complexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. This remarkable ligand-centred activation mechanism coupled to redox reactions adds a new dimension to the design of organoiridium anticancer prodrugs.
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http://dx.doi.org/10.1039/d0sc00897dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159363PMC
May 2020

DNA-Intercalative Platinum Anticancer Complexes Photoactivated by Visible Light.

Chemistry 2021 Jul 27;27(41):10711-10716. Epub 2021 May 27.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Photoactivatable agents offer the prospect of highly selective cancer therapy with low side effects and novel mechanisms of action that can combat current drug resistance. 1,8-Naphthalimides with their extended π system can behave as light-harvesting groups, fluorescent probes and DNA intercalators. We conjugated N-(carboxymethyl)-1,8-naphthalimide (gly-R-Nap) with an R substituent on the naphthyl group to photoactive diazido Pt complexes to form t,t,t-[Pt(py) (N ) (OH)(gly-R-Nap)], R=H (1), 3-NO (2) or 4-NMe (3). They show enhanced photo-oxidation, cellular accumulation and promising photo-cytotoxicity in human A2780 ovarian, A549 lung and PC3 prostate cancer cells with visible light activation, and low dark cytotoxicity. Complexes 1 and 2 exhibit pre-intercalation into DNA, resulting in enhanced photo-induced DNA crosslinking. Complex 3 has a red-shifted absorption band at 450 nm, allowing photoactivation and photo-cytotoxicity with green light.
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http://dx.doi.org/10.1002/chem.202101168DOI Listing
July 2021

Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin.

J Inorg Biochem 2021 Jun 3;219:111408. Epub 2021 Mar 3.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK. Electronic address:

Reaction of dihydroartemisinin (DHA) with 4-methyl-4'-carboxy-2,2'-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1-6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cp), or tetramethylbiphenylcyclopentadienyl (Cp), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06-9.23 μM versus 0.24-7.2 μM, respectively). Overall, the iridium complexes (1-3) are more potent compared to the rhodium derivatives (4-6), and complex 3 emerges as the most promising candidate for future studies.
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http://dx.doi.org/10.1016/j.jinorgbio.2021.111408DOI Listing
June 2021

Axial functionalisation of photoactive diazido platinum(iv) anticancer complexes.

Inorg Chem Front 2020 Oct 26;7(19):3533-3540. Epub 2020 Aug 26.

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

Mono-axial functionalised octahedral diazido Pt(iv) complexes trans, trans, trans-[Pt(py)(N)(OR)(OR)] (OR = OH and OR = anticancer agent coumarin-3 carboxylate (cou, ), pyruvate dehydrogenase kinase (PDK) inhibitors 4-phenylbutyrate (PhB, ) or dichloroacetate (DCA, )), and their di-axial functionalised analogues with OR = DCA and OR = cou (), PhB (), or DCA () have been synthesised and characterised, including the X-ray crystal structures of complexes and . These complexes exhibit dark stability and have the potential to generate cytotoxic Pt(ii) species and free radicals selectively in cancer cells when irradiated. Mono-functionalised complexes showed higher aqueous solubility and more negative reduction potentials. Mono- and di-functionalised complexes displayed higher photocytotoxicity with blue light (1 h, 465 nm, 4.8 mW cm) than the parent dihydroxido complex 1 (OR = OR = OH) in A2780 human ovarian (IC 0.9-2.9 μM for ; 0.11-0.39 μM for ) and A549 human lung cancer cells (5.4-7.8 μM for ; 1.2-2.6 μM for ) with satisfactory dark stability. Notably, no apparent dark cytotoxicity was observed in healthy lung MRC-5 fibroblasts for all complexes (IC > 20 μM). Significantly higher platinum cellular accumulation and photo-generated ROS levels were observed for the di-functionalised complexes compared with their mono-functionalised analogues when cancer cells were treated under the same concentrations.
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http://dx.doi.org/10.1039/D0QI00685HDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610473PMC
October 2020

Ligand-Controlled Reactivity and Cytotoxicity of Cyclometalated Rhodium(III) Complexes.

Eur J Inorg Chem 2020 Mar 20;2020(11-12):1052-1060. Epub 2019 Nov 20.

Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK.

We report the synthesis, characterisation and cytotoxicity of six cyclometalated rhodium(III) complexes [CpRh(C^N)Z], in which Cp = Cp*, Cp, or Cp, C^N = benzo[h]quinoline, and Z = chloride or pyridine. Three x-ray crystal structures showing the expected "piano-stool" configurations have been determined. The chlorido complexes hydrolysed faster in aqueous solution, also reacted preferentially with 9-ethyl guanine or glutathione compared to their pyridine analogues. The 1-biphenyl-2,3,4,5,-tetramethylcyclopentadienyl complex [CpRh(benzo[h]quinoline)Cl] () was the most efficient catalyst in coenzyme reduced nicotinamide adenine dinucleotide (NADH) oxidation to NAD and induced an elevated level of reactive oxygen species (ROS) in A549 human lung cancer cells. The pyridine complex [CpRh(benzo[h]quinoline)py] () was the most potent against A549 lung and A2780 ovarian cancer cell lines, being 5-fold more active than cisplatin towards A549 cells, and acted as a ROS scavenger. This work highlights a ligand-controlled strategy to modulate the reactivity and cytotoxicity of cyclometalated rhodium anticancer complexes.
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http://dx.doi.org/10.1002/ejic.201901055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610438PMC
March 2020

Osmium-arene complexes with high potency towards Mycobacterium tuberculosis.

Metallomics 2021 04;13(4)

Department of Chemistry, University of Warwick, Coventry CV4 7AL, UK.

The treatment of tuberculosis (TB) poses a major challenge as frontline therapeutic agents become increasingly ineffective with the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (Mtb). To combat this global health problem, new antitubercular agents with novel modes of action are needed. We have screened a close family of 17 organometallic half-sandwich Os(II) complexes [(arene)Os(phenyl-azo/imino-pyridine)(Cl/I)]+Y- containing various arenes (p-cymene, biphenyl, or terphenyl), and NMe2, F, Cl, or Br phenyl or pyridyl substituents, for activity towards Mtb in comparison with normal human lung cells (MRC5). In general, complexes with a monodentate iodido ligand were more potent than chlorido complexes, and the five most potent iodido complexes (MIC 1.25-2.5 µM) have an electron-donating Me2N or OH substituent on the phenyl ring. As expected, the counter anion Y (PF6-, Cl-, I-) had little effect on the activity. The pattern of potency of the complexes towards Mtb is similar to that towards human cells, perhaps because in both cases intracellular thiols are likely to be involved in their activation and their redox mechanism of action. The most active complex against Mtb is the p-cymene Os(II) NMe2-phenyl-azopyridine iodido complex (2), a relatively inert complex that also exhibits potent activity towards cancer cells. The uptake of Os from complex 2 by Mtb is rapid and peaks after 6 h, with temperature-dependence studies suggesting a major role for active transport. Significance to Metallomics Antimicrobial resistance is a global health problem. New advances are urgently needed in the discovery of new antibiotics with novel mechanisms of action. Half-sandwich organometallic complexes offer a versatile platform for drug design. We show that with an appropriate choice of the arene, an N,N-chelated ligand, and monodentate ligand, half-sandwich organo-osmium(II) complexes can exhibit potent activity towards Mycobacterium tuberculosis (Mtb), the leading cause of death from a single infectious agent. The patterns of activity of the 17 azo- and imino-pyridine complexes studied here towards Mtb and normal lung cells suggest a common redox mechanism of action involving intracellular thiols.
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http://dx.doi.org/10.1093/mtomcs/mfab007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026400PMC
April 2021

Photoactive Platinum(II) Azopyridine Complexes.

Photochem Photobiol 2021 Feb 22. Epub 2021 Feb 22.

Department of Chemistry, University of Warwick, Coventry, UK.

Platinum(II) complexes containing the strong π-acceptor N,N-chelating ligand phenylazopyridine (Ph-azpy) [Pt(p-R-Ph-azpy)X ], R = H, NMe or OH, X = Cl or N , have been synthesized and characterized to explore the effects of monodentate ligands and phenyl substituents on their absorption spectra and photoactivation. Time-dependent density functional theory calculations showed that the complexes have a low-lying unoccupied orbital with strong σ-antibonding character toward the majority of the coordination bonds. The UV-visible absorption bands were assigned as mainly ligand-centered or metal-to-ligand charge-transfer transitions, with strong contributions from the chlorido and azido groups. In complexes with substituted Ph-azpy ligands, σ-donation from NMe and OH/O groups results in a redshift of the main absorption bands compared with unsubstituted Ph-azpy complexes. The diazido complexes are photoactive in solution upon irradiation with either UVA or visible light for R = H or NMe , or UVA only when R = OH/O . Intriguingly, the phenolate group of the latter complex undergoes very slow protonation in solution. Biological screening was limited by poor solubility; however, initial tests showed that the phenolato diazido complex is rapidly taken up into the nuclei of HaCaT keratinocytes, which are stained intensely blue, and its cytotoxicity is increased upon irradiation with UVA light.
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http://dx.doi.org/10.1111/php.13405DOI Listing
February 2021

Dose- and time-dependent tolerability and efficacy of organo-osmium complex FY26 and its tissue pharmacokinetics in hepatocarcinoma-bearing mice.

Metallomics 2021 02;13(2)

Chronotherapy Team, Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Gibbett Hill Road, Coventry CV4 7AL, UK.

The organo-osmium complex [OsII(ɳ6-p-cym)(PhAzPy-NMe2)I]+ (FY26) exhibits promising in vitro antitumour activity against mouse hepatocarcinoma Hepa1-6 and other mouse or human cancer cell lines. Here, we drastically enhance water solubility of FY26 through the replacement of the PF6- counter-anion with chloride using a novel synthesis method. FY26⋅PF6 and FY26⋅Cl displayed similar in vitro cytotoxicity in two cancer cell models. We then show the moderate and late anticancer efficacy of FY26⋅PF6 and FY26⋅Cl in a subcutaneous murine hepatocarcinoma mouse model. Both efficacy and tolerability varied according to FY26 circadian dosing time in hepatocarcinoma tumour-bearing mice. Tumour and liver uptake of the drug were determined over 48 h following FY26⋅Cl administration at Zeitgeber time 6 (ZT6), when the drug is least toxic (in the middle of the light span when mice are resting). Our studies suggest the need to administer protracted low doses of FY26 at ZT6 in order to optimize its delivery schedule, for example through the use of chrono-releasing nanoparticles.
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http://dx.doi.org/10.1093/mtomcs/mfaa003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853623PMC
February 2021

Tracking Reactions of Asymmetric Organo-Osmium Transfer Hydrogenation Catalysts in Cancer Cells.

Angew Chem Int Ed Engl 2021 03 15;60(12):6462-6472. Epub 2021 Feb 15.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Most metallodrugs are prodrugs that can undergo ligand exchange and redox reactions in biological media. Here we have investigated the cellular stability of the anticancer complex [Os [(η -p-cymene)(RR/SS-MePh-DPEN)] [1] (MePh-DPEN=tosyl-diphenylethylenediamine) which catalyses the enantioselective reduction of pyruvate to lactate in cells. The introduction of a bromide tag at an unreactive site on a phenyl substituent of Ph-DPEN allowed us to probe the fate of this ligand and Os in human cancer cells by a combination of X-ray fluorescence (XRF) elemental mapping and inductively coupled plasma-mass spectrometry (ICP-MS). The BrPh-DPEN ligand is readily displaced by reaction with endogenous thiols and translocated to the nucleus, whereas the Os fragment is exported from the cells. These data explain why the efficiency of catalysis is low, and suggests that it could be optimised by developing thiol resistant analogues. Moreover, this work also provides a new way for the delivery of ligands which are inactive when administered on their own.
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http://dx.doi.org/10.1002/anie.202016456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985874PMC
March 2021

Vibrational Motions Make Significant Contributions to Sequential Methyl C-H Activations in an Organometallic Complex.

J Phys Chem Lett 2021 Jan 4;12(1):658-662. Epub 2021 Jan 4.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.

[(Pentamethylcyclopentadienyl)Rh(III)(bipyridine)(chloride)] () undergoes sequential deuteriation of its 15 Cp* CH groups in polar deuterated solvents. Vibrational spectra of and were captured via inelastic neutron spectroscopy (INS) and assigned using density functional theory (DFT) phonon calculations. These calculations were precisely weighted to the spectrometer's neutronic response. The Cp* ring behaves as a moving carousel, bringing each CH close to the Rh-OH/D center where proton abstraction occurs. Vibrations relevant for carousel movement and proximal positioning for H transfer were identified. DFT modeling uncovered changes in vibrations along the reaction path, involving a Rh(I)-fulvene intermediate. Vibronic energy contributions are large across the entire transition. Remarkably, they amount to over a 400-fold increase in the proton transfer rate. The inclusion of vibrational degrees of freedom could be applied more widely to catalysts and molecular machines to harness the energetics of these vibrations and increase their effective rates of operation.
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http://dx.doi.org/10.1021/acs.jpclett.0c03292DOI Listing
January 2021

Cu(III)-bis-thiolato complex forms an unusual mono-thiolato Cu(III)-peroxido adduct.

Chem Commun (Camb) 2021 Jan;57(1):69-72

School of Engineering, University of Warwick, Gibbet Hill Road, Coventry CV4 7Al, UK.

The stable complex [bis(toluene-3,4-dithiolato)copper(iii)][NEt3H] has been synthesised and characterised as a square-planar Cu(iii) complex by X-ray photoelectron spectroscopy, cyclic voltammetry and DFT calculations. Intriguingly, when fragmented in FTICR-MS, an unusual [(toluene-3,4-dithiolate)Cu(iii)(peroxide)]- complex is formed by reaction with oxygen. Natural 1,2-dithiolenes known to bind molybdenum might stabilise Cu(iii) in vivo.
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http://dx.doi.org/10.1039/d0cc06921cDOI Listing
January 2021

Unexpected photoactivation pathways in a folate-receptor-targeted -diazido Pt(IV) anticancer pro-drug.

Dalton Trans 2020 Sep;49(34):11828-11834

Departament de Química Inorgànica i Orgànica, Secció de Química Orgànica, IBUB, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain.

A conjugate between a photoactive trans-diazido Pt(iv) pro-drug, trans,trans,trans-[Pt(N3)2(OH)2(py)2], and folic acid has been synthesized and fully characterized by high resolution ESI-MS, NMR and UV-vis spectroscopy. Photoactivation of the Pt-folate conjugate with visible light confirmed the generation of cytotoxic Pt(ii) species capable of binding to guanine nucleobases. Importantly, photoreduction of the Pt(iv) complex triggered the photodecomposition of the folate vector into a p-aminobenzoate-containing fragment and several pterin derivatives, including 6-formylpterin. Besides exhibiting high dark stability in physiological-like conditions, the Pt-folate conjugate was ca. 2× more photocytotoxic towards MCF-7 breast cancer cell line than its parent Pt(iv) complex with a high photoselectivity index (PI > 6.9). The higher photocytotoxicity of the conjugate may be a consequence of its higher cellular accumulation and of the generation of a set of different cytotoxic species, including Pt(ii) photoproducts and several pterin derivatives, which are known to generate ROS.
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http://dx.doi.org/10.1039/d0dt02577aDOI Listing
September 2020

Structure-activity relationships for osmium(II) arene phenylazopyridine anticancer complexes functionalised with alkoxy and glycolic substituents.

J Inorg Biochem 2020 09 24;210:111154. Epub 2020 Jun 24.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. Electronic address:

Twenty-four novel organometallic osmium(II) phenylazopyridine (AZPY) complexes have been synthesised and characterised; [Os(η-arene)(5-RO-AZPY)X]Y, where arene = p-cym or bip, AZPY is functionalized with an alkoxyl (O-R, R = Me, Et, Pr, Pr, Bu) or glycolic (O-{CHCHO}R*, n = 1-4, R* = H, Me, or Et) substituent on the pyridyl ring para to the azo-bond, X is a monodentate halido ligand (Cl, Br or I), and Y is a counter-anion (PF, CFSO or IO). X-ray crystal structures of two complexes confirmed their 'half-sandwich' structures. Aqueous solubility depended on X, the AZPY substituents, arene, and Y. Iodido complexes are highly stable in water (X = I ⋙ Br > Cl), and exhibit the highest antiproliferative activity against A2780 (ovarian), MCF-7 (breast), SUNE1 (nasopharyngeal), and OE19 (oesophageal) cancer cells, some attaining nanomolar potency and good cancer-cell selectivity. Their activity and distinctive mechanism of action is discussed in relation to hydrophobicity (RP-HPLC capacity factor and Log P), cellular accumulation, electrochemical reduction (activation of azo bond), cell cycle analysis, apoptosis and induction of reactive oxygen species (ROS). Two complexes show ca. 4× higher activity than cisplatin in the National Cancer Institute (NCI) 60-cell line five-dose screen. The COMPARE algorithm of their datasets reveals a strong correlation with one another, as well as anticancer agents olivomycin, phyllanthoside, bouvardin and gamitrinib, but only a weak correlation with cisplatin, indicative of a different mechanism of action.
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http://dx.doi.org/10.1016/j.jinorgbio.2020.111154DOI Listing
September 2020

Novel tetranuclear Pd and Pt anticancer complexes derived from pyrene thiosemicarbazones.

Dalton Trans 2020 Jul;49(28):9595-9604

Department of Chemistry, University of Warwick, CV4 7AL, Coventry, UK.

Cyclometallated palladium(ii) and platinum(ii) pyrenyl-derived thiosemicarbazone (H2PrR) complexes of the type [M4(μ-S-PrR-κ3-C,N,S)4] (M = PdII, PtII; R = ethyl, cyclohexyl) have been synthesised in good yields and fully characterised. X-ray crystallography showed that the tetranuclear complex [Pt4(μ-S-PrCh-κ3-C,N,S)4](CH3)2COCHCl3 contains an eight-membered ring of alternating M-S atoms. The ethyl derivatives [M4(μ-S-PrEt-κ3-C,N,S)4] exhibit potent antiproliferative activity towards A2780 human ovarian cancer cells, with IC50 values of 1.27 μM (for M = PdII) and 0.37 μM (for M = PtII), the latter being an order of magnitude more potent than the anticancer drug cisplatin (IC50 1.20 μM). These promising complexes had low toxicity towards non-cancerous human MRC5 cells, which points towards an early indication of differential toxicity between cancer and normal cells. Experiments that investigated the effects of these tetranuclear complexes on the cell cycle, integrity of the cell membrane, and induction of apoptosis, suggested that their mechanism of action of does not involve DNA targeting, unlike cisplatin, and therefore could be promising for combatting cisplatin resistance.
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http://dx.doi.org/10.1039/d0dt01133aDOI Listing
July 2020

How promising is phototherapy for cancer?

Br J Cancer 2020 09 26;123(6):871-873. Epub 2020 Jun 26.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Oncological phototherapy, including current photodynamic therapy (PDT), developmental photoactivated chemotherapy (PACT) and photothermal therapy (PTT), shows promising photo-efficacy for superficial and internal tumours. The dual application of light and photochemotherapeutic agents allows accurate cancer targeting, low invasiveness and novel mechanisms of action. Current advances in new light sources and photoactive agents are encouraging for future development.
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http://dx.doi.org/10.1038/s41416-020-0926-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492227PMC
September 2020

Iron stored in ferritin is chemically reduced in the presence of aggregating Aβ(1-42).

Sci Rep 2020 06 25;10(1):10332. Epub 2020 Jun 25.

School of Pharmacy and Bioengineering, Keele University, Stoke-on-Trent, Staffordshire, ST4 7QB, United Kingdom.

Atypical low-oxidation-state iron phases in Alzheimer's disease (AD) pathology are implicated in disease pathogenesis, as they may promote elevated redox activity and convey toxicity. However, the origin of low-oxidation-state iron and the pathways responsible for its formation and evolution remain unresolved. Here we investigate the interaction of the AD peptide β-amyloid (Aβ) with the iron storage protein ferritin, to establish whether interactions between these two species are a potential source of low-oxidation-state iron in AD. Using X-ray spectromicroscopy and electron microscopy we found that the co-aggregation of Aβ and ferritin resulted in the conversion of ferritin's inert ferric core into more reactive low-oxidation-states. Such findings strongly implicate Aβ in the altered iron handling and increased oxidative stress observed in AD pathogenesis. These amyloid-associated iron phases have biomarker potential to assist with disease diagnosis and staging, and may act as targets for therapies designed to lower oxidative stress in AD tissue.
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http://dx.doi.org/10.1038/s41598-020-67117-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316746PMC
June 2020

Analysis of neuronal iron deposits in Parkinson's disease brain tissue by synchrotron x-ray spectromicroscopy.

J Trace Elem Med Biol 2020 Dec 20;62:126555. Epub 2020 May 20.

School of Engineering, University of Warwick, Coventry, CV4 7AL, UK.

Background: Neuromelanin-pigmented neurons, which are highly susceptible to neurodegeneration in the Parkinson's disease substantia nigra, harbour elevated iron levels in the diseased state. Whilst it is widely believed that neuronal iron is stored in an inert, ferric form, perturbations to normal metal homeostasis could potentially generate more reactive forms of iron capable of stimulating toxicity and cell death. However, non-disruptive analysis of brain metals is inherently challenging, since use of stains or chemical fixatives, for example, can significantly influence metal ion distributions and/or concentrations in tissues.

Aims: The aim of this study was to apply synchrotron soft x-ray spectromicroscopy to the characterisation of iron deposits and their local environment within neuromelanin-containing neurons of Parkinson's disease substantia nigra.

Methods: Soft x-ray spectromicroscopy was applied in the form of Scanning Transmission X-ray Microscopy (STXM) to analyse resin-embedded tissue, without requirement for chemically disruptive processing or staining. Measurements were performed at the oxygen and iron K-edges in order to characterise both organic and inorganic components of anatomical tissue using a single label-free method.

Results: STXM revealed evidence for mixed oxidation states of neuronal iron deposits associated with neuromelanin clusters in Parkinson's disease substantia nigra. The excellent sensitivity, specificity and spatial resolution of these STXM measurements showed that the iron oxidation state varies across sub-micron length scales.

Conclusions: The label-free STXM approach is highly suited to characterising the distributions of both inorganic and organic components of anatomical tissue, and provides a proof-of-concept for investigating trace metal speciation within Parkinson's disease neuromelanin-containing neurons.
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http://dx.doi.org/10.1016/j.jtemb.2020.126555DOI Listing
December 2020

Enhancing the Activity of Drugs by Conjugation to Organometallic Fragments.

Chemistry 2020 Jul 26;26(40):8676-8688. Epub 2020 May 26.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Resistance to chemotherapy is a current clinical problem, especially in the treatment of microbial infections and cancer. One strategy to overcome this is to make new derivatives of existing drugs by conjugation to organometallic fragments, either by an appropriate linker, or by direct coordination of the drug to a metal. We illustrate this with examples of conjugated organometallic metallocene sandwich and half-sandwich complexes, Ru and Os arene, and Rh and Ir cyclopentadienyl half-sandwich complexes. Ferrocene conjugates are particularly promising. The ferrocene-chloroquine conjugate ferroquine is in clinical trials for malaria treatment, and a ferrocene-tamoxifen derivative (a ferrocifen) seems likely to enter anticancer trails soon. Several other examples illustrate that organometallic conjugation can restore the activity of drugs to which resistance has developed.
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http://dx.doi.org/10.1002/chem.201904699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496994PMC
July 2020

Label-Free Nanoimaging of Neuromelanin in the Brain by Soft X-ray Spectromicroscopy.

Angew Chem Int Ed Engl 2020 07 14;59(29):11984-11991. Epub 2020 May 14.

School of Engineering, University of Warwick, Coventry, UK.

A hallmark of Parkinson's disease is the death of neuromelanin-pigmented neurons, but the role of neuromelanin is unclear. The in situ characterization of neuromelanin remains dependent on detectable pigmentation, rather than direct quantification of neuromelanin. We show that direct, label-free nanoscale visualization of neuromelanin and associated metal ions in human brain tissue can be achieved using synchrotron scanning transmission x-ray microscopy (STXM), through a characteristic feature in the neuromelanin x-ray absorption spectrum at 287.4 eV that is also present in iron-free and iron-laden synthetic neuromelanin. This is confirmed in consecutive brain sections by correlating STXM neuromelanin imaging with silver nitrate-stained neuromelanin. Analysis suggests that the 1s-σ* (C-S) transition in benzothiazine groups accounts for this feature. This method illustrates the wider potential of STXM as a label-free spectromicroscopy technique applicable to both organic and inorganic materials.
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http://dx.doi.org/10.1002/anie.202000239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383895PMC
July 2020

Metallic iron in cornflakes.

Food Funct 2020 Apr 25;11(4):2938-2942. Epub 2020 Mar 25.

School of Engineering, University of Warwick, Coventry CV4 7AL, UK.

Iron is an essential element, and cornflake-style cereals are typically fortified with iron to a level up to 14 mg iron per 100 g. Even single cornflakes exhibit magnetic behaviour. We extracted iron microparticles from samples of two own-brand supermarket cornflakes using a strong permanent magnet. Synchrotron iron K-edge X-ray absorption near-edge spectroscopic data were consistent with identification as metallic iron, and X-ray diffraction studies provided unequivocal identification of the extracted iron as body-centred cubic (BCC) α-iron. Magnetometry measurements were also consistent with ca. 14 mg per 100 g BCC iron. These findings emphasise that attention must be paid to the speciation of trace elements, in relation to their bioavailability. To mimic conditions in the stomach, we suspended the iron extract in dilute HCl (pH 1.0-2.0) at 310 K (body temperature) and found by ICP-MS that over a period of 5 hours, up to 13% of the iron dissolved. This implies that despite its metallic form in the cornflakes, the iron is potentially bioavailable for oxidation and absorption into the body.
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http://dx.doi.org/10.1039/c9fo02370dDOI Listing
April 2020

Metal complexes as a promising source for new antibiotics.

Chem Sci 2020 Mar 12;11(10):2627-2639. Epub 2020 Feb 12.

Centre for Superbug Solutions , Institute for Molecular Bioscience , The University of Queensland , St. Lucia , Queensland 4072 , Australia . Email: ; Email:

There is a dire need for new antimicrobial compounds to combat the growing threat of widespread antibiotic resistance. With a currently very scarce drug pipeline, consisting mostly of derivatives of known antibiotics, new classes of antibiotics are urgently required. Metal complexes are currently in clinical development for the treatment of cancer, malaria and neurodegenerative diseases. However, only little attention has been paid to their application as potential antimicrobial compounds. We report the evaluation of 906 metal-containing compounds that have been screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD) for antimicrobial activity. Metal-bearing compounds display a significantly higher hit-rate (9.9%) when compared to the purely organic molecules (0.87%) in the CO-ADD database. Out of 906 compounds, 88 show activity against at least one of the tested strains, including fungi, while not displaying any cytotoxicity against mammalian cell lines or haemolytic properties. Herein, we highlight the structures of the 30 compounds with activity against Gram-positive and/or Gram-negative bacteria containing Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt, with activities down to the nanomolar range against methicillin resistant (MRSA). 23 of these complexes have not been reported for their antimicrobial properties before. This work reveals the vast diversity that metal-containing compounds can bring to antimicrobial research. It is important to raise awareness of these types of compounds for the design of truly novel antibiotics with potential for combatting antimicrobial resistance.
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http://dx.doi.org/10.1039/c9sc06460eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069370PMC
March 2020

X-ray tomography of cryopreserved human prostate cancer cells: mitochondrial targeting by an organoiridium photosensitiser.

J Biol Inorg Chem 2020 03 2;25(2):295-303. Epub 2020 Mar 2.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK.

The organoiridium complex Ir[(C,N)(O,O)] (1) where C, N = 1-phenylisoquinoline and O,O = 2,2,6,6-tetramethyl-3,5-heptanedionate is a promising photosensitiser for Photo-Dynamic Therapy (PDT). 1 is not toxic to cells in the dark. However, irradiation of the compound with one-photon blue or two-photon red light generates high levels of singlet oxygen (O) (in Zhang et al. Angew Chem Int Ed Engl 56 (47):14898-14902 https://doi.org/10.1002/anie.201709082,2017), both within cell monolayers and in tumour models. Moreover, photo-excited 1 oxidises key proteins, causing metabolic alterations in cancer cells with potent antiproliferative activity. Here, the tomograms obtained by cryo-Soft X-ray Tomography (cryo-SXT) of human PC3 prostate cancer cells treated with 1, irradiated with blue light, and cryopreserved to maintain them in their native state, reveal that irradiation causes extensive and specific alterations to mitochondria, but not other cellular components. Such new insights into the effect of O generation during PDT using iridium photosensitisers on cells contribute to a detailed understanding of their cellular mode of action.
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http://dx.doi.org/10.1007/s00775-020-01761-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7082392PMC
March 2020

Metallation-Induced Heterogeneous Dynamics of DNA Revealed by Single-Molecule FRET.

Chemistry 2020 Apr 9;26(22):4980-4987. Epub 2020 Mar 9.

School of Chemistry, University of Glasgow, University Avenue, Glasgow, G12 8QQ, UK.

The metallation of nucleic acids is key to wide-ranging applications, from anticancer medicine to nanomaterials, yet there is a lack of understanding of the molecular-level effects of metallation. Here, we apply single-molecule fluorescence methods to study the reaction of an organo-osmium anticancer complex and DNA. Individual metallated DNA hairpins are characterised using Förster resonance energy transfer (FRET). Although ensemble measurements suggest a simple two-state system, single-molecule experiments reveal an underlying heterogeneity in the oligonucleotide dynamics, attributable to different degrees of metallation of the GC-rich hairpin stem. Metallated hairpins display fast two-state transitions with a two-fold increase in the opening rate to ≈2 s , relative to the unmodified hairpin, and relatively static conformations with long-lived open (and closed) states of 5 to ≥50 s. These studies show that a single-molecule approach can provide new insight into metallation-induced changes in DNA structure and dynamics.
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http://dx.doi.org/10.1002/chem.202000458DOI Listing
April 2020

Biotinylated photoactive Pt(iv) anticancer complexes.

Chem Commun (Camb) 2020 Feb 28;56(15):2320-2323. Epub 2020 Jan 28.

Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.

Novel biotinylated diazido-Pt(iv) complexes exhibit high visible light photocytotoxicity while being stable in the dark. Photocytotoxicity and cellular accumulation of all-trans-[Pt(py)(N)(biotin)(OH)] (2a) were enhanced significantly when bound to avidin; irradiation induced dramatic cellular morphological changes in human ovarian cancer cells treated with 2a.
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http://dx.doi.org/10.1039/c9cc07845bDOI Listing
February 2020

Metallocomplex-Peptide Interactions Studied by Ultrahigh Resolution Mass Spectrometry.

J Am Soc Mass Spectrom 2020 Mar 24;31(3):594-601. Epub 2020 Feb 24.

Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, United Kingdom.

The Os arene anticancer complex [(η-bip)Os(en)Cl] (Os1-Cl; where bip = biphenyl and en = ethylenediamine) binds strongly to DNA and biomolecules. Here we investigate the interaction between Os1-Cl and the model protein, BSA, using ultrahigh resolution Fourier transform-ion cyclotron resonance mass spectrometry (FT-ICR MS). The specific binding location of Os1 on BSA was investigated with the use of collisionally activated dissociation (CAD) and electron capture dissociation (ECD). CAD MS/MS was found to dissociate the osmium complex from the metallo-peptide complex readily producing unmodified fragments and losing location information. ECD MS/MS, however, successfully retains the osmium modification on the peptides upon fragmentation allowing localization of metallocomplex binding. This study reveals that lysine is a possible binding location for Os1-Cl, apart from the expected binding sites at methionine, histidine, and cysteine. Using a nano liquid chromatography (nLC)-FT-ICR ECD MS/MS study, multiple binding locations, including the N-terminus and C-terminus of digested peptides, glutamic acid, and lysine were also revealed. These results show the multitargeting binding ability of the organo-osmium compound and can be used as a standard workflow for more complex systems, e.g., metallocomplex-cell MS analysis, to evaluate their behavior toward commonly encountered biomolecules.
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http://dx.doi.org/10.1021/jasms.9b00054DOI Listing
March 2020