Publications by authors named "Guy Clarkson"

158 Publications

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

Dalton Trans 2021 Aug;50(30):10593-10607

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8335519PMC
August 2021

Synthesis of Arylidene-β-lactams via -Selective Matsuda-Heck Arylation of Methylene-β-lactams.

J Org Chem 2021 07 22;86(13):8786-8796. Epub 2021 Jun 22.

Universitaet Potsdam, Institut für Chemie, Karl-Liebknecht-Straße 24-25, D-14476 Potsdam-Golm, Germany.

-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc) under ligand-free conditions. The products, arylidene-β-lactams, were obtained in high yields as single isomers. The β-hydride elimination step of the Pd-catalyzed coupling reaction proceeds with high -regioselectivity and -stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Heck-type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail.
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http://dx.doi.org/10.1021/acs.joc.1c00638DOI Listing
July 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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361943PMC
July 2021

Synthesis and characterization of new Pd(ii) and Pt(ii) complexes with 3-substituted 1-(2-pyridyl)imidazo[1,5-a]pyridine ligands.

Dalton Trans 2021 Apr 22;50(14):4859-4873. Epub 2021 Mar 22.

Dipartimento di Chimica e Farmacia, Università degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy.

Several palladium(ii) and platinum(ii) complexes (1-20) of general formula [M(L)(X)(Y)] [M = Pd, X = Y = Cl (1-Cl-4-Cl), X = Y = OAc (1-OAc-4-OAc); M = Pt: X = Y = Cl (5-8); M = Pd, X = Cl, Y = CH (9-12); M = Pt, X = Cl, Y = CH (13-16) or X = Y = CH (17-20); n = 1-4] have been synthesized by reaction of different Pd(ii) and Pt(ii) derivatives with various 3-substituted 1-(2-pyridyl)-imidazo[1,5-a]pyridines; i.e.L = 1-(2-pyridyl)-3-arylimidazo[1,5-a]pyridine (aryl = Phenyl, L; 2-o-Tolyl, L; Mesityl, L) and 1-(2-pyridyl)-3-benzylimidazo[1,5-a]pyridine (L). Detailed spectroscopic investigation (including IR, mono- and bi-dimensional H NMR) and elemental analysis has been performed for all these species, allowing their complete characterization. L act as N,N-bidentate ligands and coordinate the metal centers in a chelate fashion through the pyridyl (N) and the pyridine-like nitrogen atom of the imidazo[1,5-a]pyridine group (N). The X-ray structural analysis performed on two of Pd(ii) and three Pt(ii) complexes, namely [Pd(L)(CH)Cl] (10), [Pd(L)(CH)Cl] (11) and [Pt(L)Cl] (5), [Pt(L)Cl] (8), [Pt(L)(CH)Cl] (14) confirmed the spectroscopic and analytical data. Finally DFT studies unveiled the structural reasons behind the inertia of the synthesised compounds toward metalation, identified as the higher angle steric strain in comparison with the analogous bipyridine complexes.
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http://dx.doi.org/10.1039/d1dt00546dDOI Listing
April 2021

Enantioselective Synthesis of Bicyclopentane-Containing Alcohols via Asymmetric Transfer Hydrogenation.

Org Lett 2021 04 5;23(8):3179-3183. Epub 2021 Apr 5.

Department of Chemistry, The University of Warwick, Coventry CV4 7AL, U.K.

Compounds a containing bicyclo[1.1.1]pentane (BCP) adjacent to a chiral center can be prepared with high enantiomeric excess through asymmetric transfer hydrogenation (ATH) of adjacent ketones. In the reduction step, the BCP occupies the position distant from the η-arene of the catalyst. The reduction was applied to the synthesis of a BCP analogue of the antihistamine drug neobenodine.
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http://dx.doi.org/10.1021/acs.orglett.1c00889DOI Listing
April 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

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

Textured Microcapsules through Crystallization.

ACS Appl Mater Interfaces 2021 Feb 22;13(4):5887-5894. Epub 2021 Jan 22.

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

This work demonstrates the fabrication of surface-textured microcapsules formed from emulsion droplets, which are stabilized by an interlocking mesh of needle-like crystals. Crystals of the small-organic-compound decane-1,10-bis(cyclohexyl carbamate) are formed within the geometric confinement of the droplets, through precipitation from a binary-solvent-dispersed phase. This binary mixture consists of a volatile solvent and nonvolatile carrier oil. Crystallization is facilitated upon supersaturation due to evaporation of the volatile solvent. Microcapsule diameter can be easily tuned using microfluidics. This approach also proves to be scalable when using conventional mixers, yielding spikey microcapsules with diameters in the range of 10-50 μm. It is highlighted that the capsule shape can be molded and arrested by jamming using recrystallization in geometric confinement. Moreover, it is shown that these textured microcapsules show a promising enhanced deposition onto a range of fabric fibers.
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http://dx.doi.org/10.1021/acsami.0c22378DOI Listing
February 2021

Synthesis of Sulfinamidines and Sulfinimidate Esters by Transfer of Nitrogen to Sulfenamides.

Org Lett 2020 09 28;22(18):7129-7134. Epub 2020 Aug 28.

Flow Chemistry and Microreactor Technology FLAME-Lab, Department of Pharmacy - Drug Sciences, University of Bari "A. Moro" Via E. Orabona 4, Bari, I - 70125, Italy.

In this work we report a new synthetic tactic for the straightforward preparation of hardly accessible sulfinamidines and sulfinamide esters, by using a simple metal-free protocol. The process is robust and uses readily available sulfenamides as the S-donor and sulfonyloxycarbamates as the N-source. The scope and mechanism have also been investigated.
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http://dx.doi.org/10.1021/acs.orglett.0c02471DOI Listing
September 2020

Asymmetric Transfer Hydrogenation: Dynamic Kinetic Resolution of α-Amino Ketones.

J Org Chem 2020 09 19;85(17):11309-11330. Epub 2020 Aug 19.

Department of Chemistry, The University of Warwick, Coventry CV4 7AL, U.K.

A series of α-amino ketones were reduced using asymmetric transfer hydrogenation (ATH) through a dynamic kinetic resolution (DKR). The protecting group was matched to the reducing agent, and following optimization, a series of substrates were investigated, giving products in high diastereoselectivity, over 99% ee in several cases and full conversion. The methodology was applied to the enantioselective synthesis of an MDM2-p53 inhibitor precursor.
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http://dx.doi.org/10.1021/acs.joc.0c01438DOI 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

Development of oxetane modified building blocks for peptide synthesis.

Org Biomol Chem 2020 07;18(28):5400-5405

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

The synthesis and use of oxetane modified dipeptide building blocks in solution and solid-phase peptide synthesis (SPPS) is reported. The preparation of building blocks containing non-glycine residues at the N-terminus in a stereochemically controlled manner is challenging. Here, a practical 4-step route to such building blocks is demonstrated, through the synthesis of dipeptides containing contiguous alanine residues. The incorporation of these new derivatives at specific sites along the backbone of an alanine-rich peptide sequence containing eighteen amino acids is demonstrated via solid-phase peptide synthesis. Additionally, new methods to enable the incorporation of all 20 of the proteinogenic amino acids into such dipeptide building blocks are reported through modifications of the synthetic route (for Cys and Met) and by changes to the protecting group strategy (for His, Ser and Thr).
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http://dx.doi.org/10.1039/d0ob01208dDOI Listing
July 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

Sulfone Group as a Versatile and Removable Directing Group for Asymmetric Transfer Hydrogenation of Ketones.

Angew Chem Int Ed Engl 2020 Aug 1;59(34):14265-14269. Epub 2020 Jul 1.

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

The sulfone functional group has a strong capacity to direct the asymmetric transfer hydrogenation (ATH) of ketones in the presence of [(arene)Ru(TsDPEN)H] complexes by adopting a position distal to the η -arene ring. This preference provides a means for the prediction of the sense of asymmetric reduction. The sulfone group also facilitates the formation of a range of reduction substrates, and its ready removal provides a route to enantiomerically enriched alcohols that would otherwise be extremely difficult to prepare by direct ATH of the corresponding ketones.
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http://dx.doi.org/10.1002/anie.202004658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496949PMC
August 2020

Synthesis of glycosyl sulfoximines by a highly chemo- and stereoselective NH- and O-transfer to thioglycosides.

Org Biomol Chem 2020 05;18(20):3893-3897

Department of Pharmacy - Drug Sciences, University of Bari "A. Moro" Via E. Orabona 4, Bari 70125, Italy.

A synthesis of unprecedented and stable glycosyl sulfoximines is reported. The developed strategies represent the first example of highly stereoselective sulfoximine formation directly from thioglycosides. This synthetic protocol has been tested on several β-thioglycosides bearing different aromatics and alkyls as S-substituents, and bearing glucose, mannose and galactose as glycosyl units. The process has been extended to a lactose derived thioglycoside and to a glucose derived sulfenamide. The process was chemo- and stereoselective, and X-ray analysis confirmed the structure and provided stereochemical information on the configuration at the sulfur atom. A model for the stereochemical outcome is proposed based on the steric environment of the sulfide.
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http://dx.doi.org/10.1039/d0ob00647eDOI Listing
May 2020

Triazole-based, optically-pure metallosupramolecules; highly potent and selective anticancer compounds.

Chem Commun (Camb) 2020 Jun;56(47):6392-6395

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

Functionalised triazole aldehydes are used in the highly selective self-assembly of water-compatible, optically pure, low symmetry Fe(ii)- and Zn(ii)-based metallohelices. Sub-micromolar antiproliferative activity is observed against various cancerous cell lines, accompanied by excellent selectivity versus non-cancerous cells and potential for synergistic combinatorial therapy with cisplatin.
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http://dx.doi.org/10.1039/d0cc02429eDOI Listing
June 2020

Asymmetric Transfer Hydrogenation of -Hydroxyphenyl Ketones: Utilizing Directing Effects That Optimize the Asymmetric Synthesis of Challenging Alcohols.

Org Lett 2020 May 16;22(9):3717-3721. Epub 2020 Apr 16.

Department of Chemistry, The University of Warwick, Coventry CV4 7AL, U.K.

A systematic range of -hydroxyphenyl ketones were reduced under asymmetric transfer hydrogenation conditions using the C3-tethered catalyst . Two directing effects, i.e., an -hydroxyphenyl coupled to a bulky aromatic on the opposite side of the ketone substrate, combine in a matched manner to deliver reduction products with very high enantiomeric excess.
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http://dx.doi.org/10.1021/acs.orglett.0c01213DOI Listing
May 2020

Readily accessible sp-rich cyclic hydrazine frameworks exploiting nitrogen fluxionality.

Chem Sci 2020 Feb 2;11(6):1636-1642. Epub 2020 Jan 2.

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

Increased molecular complexity correlates with improved chances of success in the drug development process. Here, a strategy for the creation of sp-rich, non-planar heterocyclic scaffolds suitable for drug discovery is described that obviates the need to generate multiple stereogenic centers with independent control. Asymmetric transfer hydrogenation using a tethered Ru-catalyst is used to efficiently produce a range of enantiopure cyclic hydrazine building blocks (up to 99% ee). Iterative C-N functionalization at the two nitrogen atoms of these compounds produces novel hydrazine and hydrazide based chemical libraries. Wide chemical diversification is possible through variation in the hydrazine structure, use of different functionalization chemistries and coupling partners, and controlled engagement of each nitrogen of the hydrazine in turn. Principal Moment of Inertia (PMI) analysis of this small hydrazine library reveals excellent shape diversity and three-dimensionality. NMR and crystallographic studies confirm these frameworks prefer to orient their substituents in three-dimensional space under the control of a single stereogenic center through exploitation of the fluxional behavior of the two nitrogen atoms.
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http://dx.doi.org/10.1039/c9sc04849aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069508PMC
February 2020

Metallohelices that kill Gram-negative pathogens using intracellular antimicrobial peptide pathways.

Chem Sci 2019 Nov 5;10(42):9708-9720. Epub 2019 Sep 5.

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

A range of new water-compatible optically pure metallohelices - made by self-assembly of simple non-peptidic organic components around Fe ions - exhibit similar architecture to some natural cationic antimicrobial peptides (CAMPs) and are found to have high, structure-dependent activity against bacteria, including clinically problematic Gram-negative pathogens. A key compound is shown to freely enter rapidly dividing cells without significant membrane disruption, and localise in distinct foci near the poles. Several related observations of CAMP-like mechanisms are made biophysical measurements, whole genome sequencing of tolerance mutants and transcriptomic analysis. These include: high selectivity for binding of G-quadruplex DNA over double stranded DNA; inhibition of both DNA gyrase and topoisomerase I ; curing of a plasmid that contributes to the very high virulence of the strain used; activation of various two-component sensor/regulator and acid response pathways; and subsequent attempts by the cell to lower the net negative charge of the surface. This impact of the compound on multiple structures and pathways corresponds with our inability to isolate fully resistant mutant strains, and supports the idea that CAMP-inspired chemical scaffolds are a realistic approach for antimicrobial drug discovery, without the practical barriers to development that are associated with natural CAMPS.
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http://dx.doi.org/10.1039/c9sc03532jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977464PMC
November 2019

Strategies for conjugating iridium(III) anticancer complexes to targeting peptides via copper-free click chemistry.

Inorganica Chim Acta 2020 Apr 23;503:119396. Epub 2019 Dec 23.

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

We report the synthesis and characterization of novel pentamethylcyclopentadienyl (Cp*) iridium(III) complexes [(Cp*)Ir(4-methyl-4'-carboxy-2,2'-bipyridine)Cl]PF6 (Ir-I), the product (Ir-II) from amide coupling of Ir-I to dibenzocyclooctyne-amine, and its conjugate (Ir-CP) with the cyclic nona-peptide c(CRWYDENAC). The familiar three-legged 'piano-stool' configuration for complex Ir-I was confirmed by its single crystal X-ray structure. Significantly, copper-free click strategy has been developed for site-specific conjugation of the parent complex Ir-I to the tumour targeting nona-cyclic peptide. The approach consisted of two steps: (i) the carboxylic acid group of the bipyridine ligand in complex Ir-I was first attached to an amine functionalized dibenzocyclooctyne group via amide formation to generate complex Ir-II; and (ii) the alkyne bond of dibenzocyclooctyne in complex Ir-II underwent a subsequent strain-promoted copper-free cycloaddition with the azide group of the modified peptide. Interestingly, while complex Ir-I was inactive towards A2780 human ovarian cancer cells, complex Ir-II exhibited moderate cytotoxic activity. Targeted complexes such as Ir-CP offer scope for enhanced activity and selectivity of this class of anticancer complexes.
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http://dx.doi.org/10.1016/j.ica.2019.119396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610455PMC
April 2020

Platinum(iv) dihydroxido diazido -(heterocyclic)imine complexes are potently photocytotoxic when irradiated with visible light.

Chem Sci 2019 Oct 8;10(37):8610-8617. Epub 2019 Aug 8.

Chemistry Research Laboratory , University of Oxford , 12 Mansfield Road , Oxford , OX1 3TA , UK . Email: ; Email: ; Tel: +44 (0)1865 285131.

A series of -di-(-heterocyclic)imine dihydroxido diazido Pt complexes of the form ,,-[Pt(N)(OH)(L)(L)] where L = pyridine, 2-picoline, 3-picoline, 4-picoline, thiazole and 1-methylimidazole have been synthesised and characterised, and their photochemical and photobiological activity evaluated. Notably, complexes (L = py, L = 3-pic) and (L = L = 4-pic) were potently phototoxic following irradiation with visible light (420 nm), with IC values of 4.0 μM and 2.1 μM respectively (A2780 cancer cell line), demonstrating greater potency than the previously reported complex (L = L = py; 6.7 μM); whilst also being minimally toxic in the absence of irradiation. Complexes with mixed -(heterocyclic)imine ligands and (L = py, L = 4-pic) were particularly photocytotoxic towards cisplatin resistant (A2780cis) cell lines. Complex (L = py, L = 2-pic) was comparatively less photocytotoxic (IC value 14.5 μM) than the other complexes, despite demonstrating the greatest absorbance at the irradiation wavelength and the fastest half-life for loss of the N → Pt LMCT transition upon irradiation ( = 463 nm) in aqueous solution. Complex (X = X = thiazole) although potently phototoxic (2.4 μM), was also toxic towards cells in the absence of irradiation.
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http://dx.doi.org/10.1039/c9sc02644dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6844273PMC
October 2019

Targeted photoredox catalysis in cancer cells.

Nat Chem 2019 11 23;11(11):1041-1048. Epub 2019 Sep 23.

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

Hypoxic tumours are a major problem for cancer photodynamic therapy. Here, we show that photoredox catalysis can provide an oxygen-independent mechanism of action to combat this problem. We have designed a highly oxidative Ir(III) photocatalyst, [Ir(ttpy)(pq)Cl]PF ([1]PF, where 'ttpy' represents 4'-(p-tolyl)-2,2':6',2''-terpyridine and 'pq' represents 3-phenylisoquinoline), which is phototoxic towards both normoxic and hypoxic cancer cells. Complex 1 photocatalytically oxidizes 1,4-dihydronicotinamide adenine dinucleotide (NADH)-an important coenzyme in living cells-generating NAD radicals with a high turnover frequency in biological media. Moreover, complex 1 and NADH synergistically photoreduce cytochrome c under hypoxia. Density functional theory calculations reveal π stacking in adducts of complex 1 and NADH, facilitating photoinduced single-electron transfer. In cancer cells, complex 1 localizes in mitochondria and disrupts electron transport via NADH photocatalysis. On light irradiation, complex 1 induces NADH depletion, intracellular redox imbalance and immunogenic apoptotic cancer cell death. This photocatalytic redox imbalance strategy offers a new approach for efficient cancer phototherapy.
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http://dx.doi.org/10.1038/s41557-019-0328-4DOI Listing
November 2019

A hydrothermally stable ytterbium metal-organic framework as a bifunctional solid-acid catalyst for glucose conversion.

Chem Commun (Camb) 2019 Sep;55(76):11446-11449

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

Yb6(BDC)7(OH)4(H2O)4 contains both bridging hydroxyls and metal-coordinated waters, possessing Brønsted and Lewis acid sites. The material crystallises from water at 200 °C. Using the solid as a heterogenous catalyst, glucose is converted into 5-hydroxymethylfurfural, via fructose, with a total selectivity of ∼70% after 24 hours at 140 °C in water alone: the material is recyclable with no loss of crystallinity.
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http://dx.doi.org/10.1039/c9cc05364fDOI Listing
September 2019

The structure of the anti-aging agent J147 used for treating Alzheimer's disease.

Acta Crystallogr C Struct Chem 2019 03 12;75(Pt 3):271-276. Epub 2019 Feb 12.

Instituto de Química Médica, Centro de Química Orgánica Manuel Lora-Tamayo, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain.

The molecular structure of the anti-aging agent J147 [systematic name: (E)-N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3-methoxybenzylidene)acetohydrazide], CHFNO, has been determined at 150 K. The crystal structure corresponds to the minimum-energy conformation in the gas phase calculated by density functional theory (DFT). 15 other conformations have been calculated and compared with the minimum, denoted 1111. NMR spectroscopic data have been obtained and compared with those from Gauge Independent Atomic Orbital (GIAO) calculations. DFT calculations allow the reduction of the 16 possible rotamers to the four most stable (i.e. 1111, 1112, 1121 and 1222); in addition, the calculated barriers connecting these minima are low enough to permit their interconversion. Comparison of the NMR spectroscopic results, both experimental and calculated, point to the 1121 isomer being present in chloroform solution.
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http://dx.doi.org/10.1107/S205322961900144XDOI Listing
March 2019

The role of symmetric functionalisation on photoisomerisation of a UV commercial chemical filter.

Phys Chem Chem Phys 2019 Jul;21(26):14350-14356

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

Photoisomerisation has been shown to be an efficient excited-state relaxation mechanism for a variety of nature-based and artificial-based molecular systems. Here we report on the excited-state relaxation dynamics and consequent photostability of a symmetrically functionalised cinnamate by transient electronic absorption spectroscopy, along with complementary computational and steady-state spectroscopy methods. The findings are then discussed in comparison to 2-ethylhexyl-E-4-methoxycinnamate, a structurally related 'off the shelf' chemical filter present in commercial sunscreens with a similar absorption profile. The present study allows for a like-for-like comparison beween 2-ethylhexyl-E-4-methoxycinnamate and the functionalised cinnamate, driven by the need to enhance solar protection across both the UVA and UVB regions of the electromagnetic spectrum.
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http://dx.doi.org/10.1039/c8cp06536eDOI Listing
July 2019

Structural analysis of peptides modified with organo-iridium complexes, opportunities from multi-mode fragmentation.

Analyst 2019 Feb;144(5):1575-1581

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

The most widely used anticancer drugs are platinum complexes, but complexes of other transition metals also show promise and may widen the spectrum of activity, reduce side-effects, and overcome resistance. The latter include organo-iridium(iii) 'piano-stool' complexes. To understand their mechanism of action, it is important to discover how they bind to biomolecules and how binding is affected by functionalisation of the ligands bound to iridium. We have characterised, by MS and MS/MS techniques, unusual adducts from reactions between 3 novel iridium(iii) anti-cancer complexes each possessing reactive sites both at the metal (coordination by substitution of a labile chlorido ligand) and on the ligand (covalent bond formation involving imine formation by one or two aldehyde functions). Peptide modification by the metal complex had a drastic effect on both Collisonally Activated Dissociation (CAD) and Electron Capture Dissociation (ECD) MS/MS behaviour, tuning requirements, and fragmentation channels. CAD MS/MS was effective only when studying the covalent condensation products. ECD MS/MS, although hindered by electron-quenching at the Iridium complex site, was suitable for studying many of the species observed, locating the modification sites, and often identifying them to within a single amino acid residue.
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http://dx.doi.org/10.1039/c8an02094aDOI Listing
February 2019

Nucleus-Targeted Organoiridium-Albumin Conjugate for Photodynamic Cancer Therapy.

Angew Chem Int Ed Engl 2019 02 21;58(8):2350-2354. Epub 2019 Jan 21.

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

An organoiridium-albumin bioconjugate (Ir1-HSA) was synthesized by reaction of a pendant maleimide ligand with human serum albumin. The phosphorescence of Ir1-HSA was enhanced significantly compared to parent complex Ir1. The long phosphorescence lifetime and high O quantum yield of Ir1-HSA are highly favorable properties for photodynamic therapy. Ir1-HSA mainly accumulated in the nucleus of living cancer cells and showed remarkable photocytotoxicity against a range of cancer cell lines and tumor spheroids (light IC ; 0.8-5 μm, photo-cytotoxicity index PI=40-60), while remaining non-toxic to normal cells and normal cell spheroids, even after photo-irradiation. This nucleus-targeting organoiridium-albumin is a strong candidate photosensitizer for anticancer photodynamic therapy.
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http://dx.doi.org/10.1002/anie.201813002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468315PMC
February 2019

Photoactivatable Cell-Selective Dinuclear trans-Diazidoplatinum(IV) Anticancer Prodrugs.

Inorg Chem 2018 Nov 26;57(22):14409-14420. Epub 2018 Oct 26.

Department of Chemistry , University of Warwick , Coventry CV4 7AL , U.K.

A series of dinuclear octahedral Pt complexes trans, trans, trans-[{Pt(N)(py)(OH)(OC(O)CHCHC(O)NH)}R] containing pyridine (py) and bridging dicarboxylate [R = -CHCH- (1), trans-1,2-CH- (2), p-CH- (3), -CHCHCHCH- (4)] ligands have been synthesized and characterized, including the X-ray crystal structures of complexes 1·2MeOH and 4, the first photoactivatable dinuclear Pt complexes with azido ligands. The complexes are highly stable in the dark, but upon photoactivation with blue light (420 nm), they release the bridging ligand and mononuclear photoproducts. Upon irradiation with blue light (465 nm), they generate azidyl and hydroxyl radicals, detected using a 5,5-dimethyl-1-pyrroline N-oxide electron paramagnetic resonance spin trap, accompanied by the disappearance of the ligand-to-metal charge-transfer (N → Pt) band at ca. 300 nm. The dinuclear complexes are photocytotoxic to human cancer cells (465 nm, 4.8 mW/cm, 1 h), including A2780 human ovarian and esophageal OE19 cells with IC values of 8.8-78.3 μM, whereas cisplatin is inactive under these conditions. Complexes 1, 3, and 4 are notably more photoactive toward cisplatin-resistant ovarian A2780cis compared to A2780 cells. Remarkably, all of the complexes were relatively nontoxic toward normal cells (MRC5 lung fibroblasts), with IC values >100 μM, even after irradiation. The introduction of an aromatic bridging ligand (3) significantly enhanced cellular uptake. The populations in the stages of the cell cycle remained unchanged upon treatment with complexes in the dark, while the population of the G2/M phase increased upon irradiation, suggesting that DNA is a target for these photoactivated dinuclear Pt complexes. Liquid chromatography-mass spectrometry data show that the photodecomposition pathway of the dinuclear complexes results in the release of two molecules of mononuclear platinum(II) species. As a consequence, DNA binding of the dinuclear complexes after photoactivation in cell-free media is, in several respects, qualitatively similar to that of the photoactivated mononuclear complex FM-190. After photoactivation, they were 2-fold more effective in quenching the fluorescence of EtBr bound to DNA, forming DNA interstrand cross-links and unwinding DNA compared to the photoactivated FM-190.
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http://dx.doi.org/10.1021/acs.inorgchem.8b02599DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257630PMC
November 2018
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