Publications by authors named "Nicola J Farrer"

27 Publications

  • Page 1 of 1

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

Solvent-Dependent Reactivity and Photochemistry of Dinuclear and Mononuclear Platinum(IV) Azido Triazaolato Complexes.

Eur J Inorg Chem 2021 Apr 16;2021(14):1397-1404. Epub 2021 Mar 16.

Chemistry Research Laboratory University of Oxford 12 Mansfield Road Oxford OX1 3TA United Kingdom.

Reaction between the platinum(IV) azido complex ,-[Pt(py)(N)(OH)] () and 1,4-diphenyl-2-butyne-1,4-dione in MeCN produces the intermediate peroxide-bridged dimeric platinum(IV) azido triazolato species (), which has been characterised by X-ray crystallography. However, if the reaction between and is conducted in MeOH it results in decomposition. Over time in MeCN, dimer () converts into mononuclear complexes ,-[Pt(py)(N)(triazole)(OH)] (/), which are in dynamic exchange. If resuspended in protic solvents (MeOH,HO), / undergo a slow (22 d) irreversible rearrangement to a cyclised platinum(IV) species which contains a formally N,O-chelated ligand. Conversion of / to in -MeOH can be accelerated (384x) by irradiation with visible light, although continued irradiation also produces N and OH radicals, and the [-N] species can be readily detected by ESI-MS. Solvent choice significantly effects both the cycloaddition reaction between and , and the stability of the resultant complexes.
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http://dx.doi.org/10.1002/ejic.202100041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251955PMC
April 2021

Cell-permeable lanthanide-platinum(IV) anti-cancer prodrugs.

Dalton Trans 2021 Jun;50(25):8761-8767

Chemistry Research Laboratory, University of Oxford, Mansfield Road, OX1 3TA, UK.

Platinum compounds are a vital part of our anti-cancer arsenal, and determining the location and speciation of platinum compounds is crucial. We have synthesised a lanthanide complex bearing a salicylic group (Ln = Gd, Eu) which demonstrates excellent cellular accumulation and minimal cytotoxicity. Derivatisation enabled access to bimetallic lanthanide-platinum(ii) and lanthanide-platinum(iv) complexes. Luminescence from the europium-platinum(iv) system was quenched, and reduction to platinum(ii) with ascorbic acid resulted in a "switch-on" luminescence enhancement. We used diffusion-based 1H NMR spectroscopic methods to quantify cellular accumulation. The gadolinium-platinum(ii) and gadolinium-platinum(iv) complexes demonstrated appreciable cytotoxicity. A longer delay following incubation before cytotoxicity was observed for the gadolinium-platinum(iv) compared to the gadolinium-platinum(ii) complex. Functionalisation with octanoate ligands resulted in enhanced cellular accumulation and an even greater latency in cytotoxicity.
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http://dx.doi.org/10.1039/d1dt01688aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237448PMC
June 2021

Oxaliplatin and [Pt(R,R-DACH)(panobinostat)] show nanomolar cytotoxicity towards diffuse intrinsic pontine glioma (DIPG).

Dalton Trans 2020 May 16;49(17):5703-5710. Epub 2020 Apr 16.

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

We report the synthesis of two novel platinum(ii) complexes which incorporate histone deacetylase (HDAC) inhibitors: [Pt(R,R-DACH)(Sub)] (1), [Pt(R,R-DACH)(panobinostat)] (2), where SubH = suberoyl-bis-hydroxamic acid; DACH = (1R,2R)-(-)-1,2-diaminocyclohexane and panobinostat = (E)-N-hydroxy-3-[4-[[2-(2-methyl-1H-indol-3-yl)ethylamino]methyl]phenyl]prop-2-enamide. Complexes 1 and 2 were characterised by H, C, Pt NMR spectroscopy and ESI-MS. Whilst oxaliplatin demonstrated considerable cytotoxicity in two patient-derived low-passage paediatric glioma DIPG cell lines (IC values of 0.333 μM in SU-DIPG-IV, and 0.135 μM in SU-DIPG-XXI), complex 2 showed even greater cytotoxicities, with IC values of 0.021 μM (SU-DIPG-IV), 0.067 μM (BIOMEDE 194) and 0.009 μM (SU-DIPG-XXI). Complex 2 also demonstrated superior aqueous solubility in comparison to panobinostat. Complex 2 released free intact panobinostat under HPLC conditions, as determined by ESI-MS. Incubation of solutions of oxaliplatin (HO) and panobinostat (DMF) resulted in instantaneous reactivity and precipitation of a panobinostat derivative which was not a platinum complex; the same reactivity was not observed between carboplatin and panobinostat.
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http://dx.doi.org/10.1039/c9dt04862fDOI Listing
May 2020

Enhancing P NMR relaxation rates with a kinetically inert gadolinium complex.

Dalton Trans 2020 Mar;49(9):2989-2993

British Heart Foundation Experimental MR Unit (BMRU), University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK and Leeds Institute of Cardiovascular and Metabolic Medicine, Biomedical Imaging Science Department, University of Leeds, Clarendon Way, Leeds, LS2 9JT, UK.

The kinetically stable heptadentate gadolinium complex Gd.pDO3A (1.Gd) demonstrates significant 31P nuclear magnetic resonance (NMR) relaxation enhancement of biologically relevant phosphate species; adenosine triphosphate (ATP), phosphocreatine (PCr) and inorganic phosphate. Gd.pDO3A (1.Gd) binds these species in fast exchange, enabling the relaxation of the bulk phosphate species in solution. This gives rise to 31P relaxation enhancements up to 250-fold higher than those observed for 31P relaxation enhancements with the commercial MRI contrast agent Gd.DOTA (DOTAREM), 2. Gd.pDO3A-like complexes may have potential applications as 31P magnetic resonance contrast agents, since shortening the T1 relaxation time of phosphate species would reduce the time needed to acquire 31P-MR spectra.
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http://dx.doi.org/10.1039/c9dt03761fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610995PMC
March 2020

Exploiting azide-alkyne click chemistry in the synthesis, tracking and targeting of platinum anticancer complexes.

Curr Opin Chem Biol 2020 04 13;55:59-68. Epub 2020 Jan 13.

Department of Chemistry, RCSI, 123 St. Stephens Green, Dublin 2, Ireland; SSPC, Synthesis and Solid State Pharmaceutical Centre, Ireland. Electronic address:

Click chemistry is fundamentally important to medicinal chemistry and chemical biology. It represents a powerful and versatile tool, which can be exploited to develop novel Pt-based anticancer drugs and to better understand the biological effects of Pt-based anticancer drugs at a cellular level. Innovative azide-alkyne cycloaddition-based approaches are being used to functionalise Pt-based complexes with biomolecules to enhance tumour targeting. Valuable information in relation to the mechanisms of action and resistance of Pt-based drugs is also being revealed through click-based detection, isolation and tracking of Pt drug surrogates in biological and cellular environments. Although less well-explored, inorganic Pt-click reactions enable synthesis of novel (potentially multimetallic) Pt complexes and provide plausible routes to introduce functional groups and monitoring Pt-azido drug localisation.
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http://dx.doi.org/10.1016/j.cbpa.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254056PMC
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

A visible-light photoactivatable di-nuclear Pt triazolato azido complex.

Chem Commun (Camb) 2019 Sep;55(75):11287-11290

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

A novel PtIV triazolato azido complex [3]-[N1,N3] has been synthesised via a strain-promoted double-click reaction (SPDC) between a PtIV azido complex (1) and the Sondheimer diyne (2). Photoactivation of [3]-[N1,N3] with visible light (452 nm) in the presence of 5'-guanosine monophosphate (5'-GMP) produced both PtIV and PtII 5'-GMP species; EPR spectroscopy confirmed the production of both azidyl and hydroxyl radicals. Spin-trapping of photogenerated radicals - particularly hydroxyl radicals - was significantly reduced in the presence of 5'-GMP.
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http://dx.doi.org/10.1039/c9cc05310gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984334PMC
September 2019

A novel Pt(iv) mono azido mono triazolato complex evolves azidyl radicals following irradiation with visible light.

Dalton Trans 2019 May;48(19):6416-6420

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

The platinum(iv) azido complex trans,trans,trans-[PtIV(N3)2(OH)2(py)2] (1) undergoes cycloaddition with 1,4-diphenyl-2-butyne-1,4-dione (2) under mild, catalyst-free conditions, affording a number of mono and bis click products. The major mono click product (3) exists in MeCN as an equilibrium mixture between two species; 3a and 3b rapidly interconvert through nucleophilic attack of the axial Pt-OH group at the adjacent Ph-CO group. The kinetic and thermodynamic parameters for this interconversion have been measured by selective saturation-transfer NMR spectroscopic experiments and are consistent with cyclisation at the Pt centre. Complex 3b was also characterised by X-ray crystallography. Visible light irradiation (440-480 nm) of 3 in d3-MeCN produces azidyl radicals (N3˙), as demonstrated by EPR spin-trapping with DMPO; no generation of hydroxyl radicals was observed. 1H-195Pt HMBC NMR confirmed that the photoproducts were PtIV rather than PtII species, and HPLC was consistent with these being [3-N3]+ species; no facile photoejection of the triazolato ligand was observed, consistent with MS/MS fragmentation of 3. When 3 was irradiated in the presence of 5'-GMP, no 5'-GMP photoproducts were observed, suggesting that complex 3 is likely to exhibit significantly simplified biological activity (release of azidyl radicals but not DNA binding) compared with complex 1.
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http://dx.doi.org/10.1039/c9dt01156kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984332PMC
May 2019

INDIANA: An in-cell diffusion method to characterize the size, abundance and permeability of cells.

J Magn Reson 2019 05 6;302:1-13. Epub 2019 Jan 6.

Department of Chemistry, Physical and Theoretical Chemistry Laboratory, University of Oxford, South Parks Road, Oxford OX1 3QZ, United Kingdom. Electronic address:

NMR and MRI diffusion experiments contain information describing the shape, size, abundance, and membrane permeability of cells although extracting this information can be challenging. Here we present the INDIANA (IN-cell DIffusion ANAlysis) method to simultaneously and non-invasively measure cell abundance, effective radius, permeability and intrinsic relaxation rates and diffusion coefficients within the inter- and intra-cellular populations. The method couples an experimental dataset comprising stimulated-echo diffusion measurements, varying both the gradient strength and the diffusion delay, together with software to fit a model based on the Kärger equations to robustly extract the relevant parameters. A detailed error analysis is presented by comparing the results from fitting simulated data from Monte Carlo simulations, establishing its effectiveness. We note that for parameters typical of mammalian cells the approach is particularly effective, and the shape of the underlying cells does not unduly affect the results. Finally, we demonstrate the performance of the experiment on systems of suspended yeast and mammalian cells. The extracted parameters describing cell abundance, size, permeability and relaxation are independently validated.
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http://dx.doi.org/10.1016/j.jmr.2018.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611012PMC
May 2019

Platinum(iv) azido complexes undergo copper-free click reactions with alkynes.

Dalton Trans 2018 Aug;47(31):10553-10560

Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

We report our investigations into the first examples of copper-free 1,3-dipolar cycloaddition (click) reactions of electrophiles with a PtIV azido complex. The Pt-IV azido complex trans, trans, trans-[PtIV(py)2(N3)2(OH)2] (1) was reactive towards dimethyl acetylenedicarboxylate (DMAD) (2), diethyl acetylenedicarboxylate DEACD (3), N-[(1R,8S,9s)-bicyclo[6.1.0]non-4-yn-9-ylmethyloxycarbonyl]-1,8-diamino-3,6-dioxaoctane (BCN) (11) and dibenzocyclooctyne-amine (DBCO) (12) resulting in formation of the corresponding mono (a) and bis-substituted (b) complexes. Complexes of 2 undergo further reactions between the Pt centre and the carbonyl group to form 2a' and 2b'. This is not seen for the products of the corresponding PtII azido complex trans-[Pt(py)2(N3)2] with acetylene 2. Novel complexes 2a', 2b', 11a and 11b have been characterised by multinuclear NMR, IR and UV-vis spectroscopy and ESI-MS. These reactions represent new synthetic routes to novel Pt(iv) complexes.
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http://dx.doi.org/10.1039/c7dt04183gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083821PMC
August 2018

De novo generation of singlet oxygen and ammine ligands by photoactivation of a platinum anticancer complex.

Angew Chem Int Ed Engl 2013 Dec 25;52(51):13633-7. Epub 2013 Oct 25.

Department of Chemistry, University of Warwick, Coventry CV4 7AL (United Kingdom); Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Analytical Chemistry for Living Biosystems, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 (P.R. China).

Worth the excitement: Highly reactive oxygen and nitrogen species are generated by photoactivation of the anticancer platinum(IV) complex trans,trans,trans-[Pt(N3 )2 (OH)2 (MA)(Py)] (MA=methylamine, Py=pyridine). Singlet oxygen is formed from the hydroxido ligands and not from dissolved oxygen, and ammine ligands are products from the conversion of azido ligands to nitrenes. Both processes can induce oxidation of guanine.
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http://dx.doi.org/10.1002/anie.201307505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230391PMC
December 2013

Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts.

Chemistry 2013 Jul 3;19(29):9578-91. Epub 2013 Jun 3.

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

Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable Pt(IV) prodrugs offer the potential of targeted drug release and new mechanisms of action. We report the synthesis, X-ray crystallographic and spectroscopic properties of photoactivatable diazido complexes trans,trans,trans-[Pt(N3)2(OH)2(MA)(Py)] (1; MA=methylamine, Py=pyridine) and trans,trans,trans-[Pt(N3)2(OH)2(MA)(Tz)] (2; Tz=thiazole), and interpret their photophysical properties by TD-DFT modelling. The orientation of the azido groups is highly dependent on H bonding and crystal packing, as shown by polymorphs 1p and 1q. Complexes 1 and 2 are stable in the dark towards hydrolysis and glutathione reduction, but undergo rapid photoreduction with UVA or blue light with minimal amine photodissociation. They are over an order of magnitude more potent towards HaCaT keratinocytes, A2780 ovarian, and OE19 oesophageal carcinoma cells than cisplatin and show particular potency towards cisplatin-resistant human ovarian cancer cells (A2780cis). Analysis of binding to calf-thymus (CT), plasmids, oligonucleotide DNA and individual nucleotides reveals that photoactivated 1 and 2 form both mono- and bifunctional DNA lesions, with preference for G and C, similar to transplatin, but with significantly larger unwinding angles and a higher percentage of interstrand cross-links, with evidence for DNA strand cross-linking further supported by a comet assay. DNA lesions of 1 and 2 on a 50 bp duplex were not recognised by HMGB1 protein, in contrast to cisplatin-type lesions. The photo-induced platination reactions of DNA by 1 and 2 show similarities with the products of the dark reactions of the Pt(II) compounds trans-[PtCl2(MA)(Py)] (5) and trans-[PtCl2(MA)(Tz)] (6). Following photoactivation, complex 2 reacted most rapidly with CT DNA, followed by 1, whereas the dark reactions of 5 and 6 with DNA were comparatively slow. Complexes 1 and 2 can therefore give rapid potent photocytotoxicity and novel DNA lesions in cancer cells, with no activity in the absence of irradiation.
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http://dx.doi.org/10.1002/chem.201300374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280898PMC
July 2013

Photo-isomerisation of alkenyl complexes of platinum(II): structural, spectroscopic, kinetic and computational investigations.

Dalton Trans 2013 May;42(19):6840-51

Dipartimento di Chimica, Università degli Studi Aldo Moro di Bari, Via E. Orabona 4, I-70125 Bari, Italy.

In this work UVA and blue light have been used to study photo-isomerisation about the C=C double bond in complexes of the type [PtCl(-CH=CHAr)(tmeda)] [Ar = C6H5, (E)-2a; 4-CH3O-C6H4, (E)-2b; 3-NO2-C6H4, (E)-2c; and 3-CH3O-C6H4, (E)-2d]. The progress of the reaction has been monitored by NMR spectroscopy following irradiation of the NMR sample. The NMR data have been complemented with X-ray diffractometric analysis of compounds (E)-2a-c and (Z)-2a. The kinetic data clearly indicate that a monomolecular mechanism is operating with the energy of the irradiating light influencing the rate of isomerisation but not the equilibrium composition, which is only slightly in favour of the Z isomer. DFT and TD-DFT theoretical investigations have been carried out to elucidate the nature of the main electronic transitions in the UV-Vis region and the mechanism of the photo-isomerisation reaction appears to proceed through a C=C bond twist process similar to that involved in purely organic molecules such as stilbene. In the Z isomer, one ortho proton of the phenyl group can come close to platinum (Pt···H(ortho) distance of 2.632 Å in (Z)-2a). In the case of 2c, the difference in chemical shift between the two ortho protons varies from 3.30 ppm in the Z isomer, where interaction with Pt is possible, to 0.60 ppm in the E isomer, where such interaction cannot take place. The analysis of the DFT orbitals indicates that the most shifted H(ortho) is that with a greater positive charge, pointing to an H-bond type of interaction.
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http://dx.doi.org/10.1039/c3dt32354dDOI Listing
May 2013

Two-photon-activated ligand exchange in platinum(II) complexes.

Angew Chem Int Ed Engl 2012 Nov 9;51(45):11263-6. Epub 2012 Oct 9.

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

Two photons are better than one: a square-planar Pt(II) complex with derivatized pyridine ligands was synthesized, which undergoes two-photon-induced ligand substitution with 600-740 nm light. Linear and quadratic density functional response theory allowed identification of the electronic transitions involved.
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http://dx.doi.org/10.1002/anie.201206283DOI Listing
November 2012

Tryptophan switch for a photoactivated platinum anticancer complex.

J Am Chem Soc 2012 Oct 25;134(40):16508-11. Epub 2012 Sep 25.

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

The octahedral Pt(IV) complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(py)(2)] (1) is potently cytotoxic to cancer cells when irradiated with visible (blue) light. We show that the acute photocytotoxicity can be switched off by low doses (500 μM) of the amino acid l-tryptophan. EPR and NMR spectroscopic experiments using spin traps show that l-Trp quenches the formation of azidyl radicals, probably by acting as an electron donor. l-Trp is well-known as a mediator of electron transfer between distant electron acceptor/donor centers in proteins, and such properties may make the free amino acid clinically useful for controlling the activity of photochemotherapeutic azido Pt(IV) drugs. Since previous work has demonstrated the ability of photoactivated 1 to platinate DNA, this suggests that the high potency of such photoactive platinum complexes is related to their dual attack on cancer cells by radicals and Pt(II) photoproducts.
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http://dx.doi.org/10.1021/ja3074159DOI Listing
October 2012

A computational approach to tuning the photochemistry of platinum(IV) anticancer agents.

Chemistry 2012 Aug 13;18(34):10630-42. Epub 2012 Jul 13.

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

Diazido Pt(IV) complexes are inert stable prodrugs that can be photoactivated to produce Pt(II) species with promising anticancer activity. Our studies of the photochemistry of Pt(IV) complexes, [Pt(X)(2) (Y)(2) (Z)(2) ](0/-1) (X=N-ligands (NH(3) , pyridine, etc.)/S(CH(3) )(2) /H(-) , Y=(pseudo)halogen (N(3) (-) , I(-) ), Z=OR(-) , R=H, Ac) by time-dependent density functional theory (TDDFT) show close agreement with spectroscopic data. Broad exploration of cis/trans geometries, trans influences, the nature of the OR(-) and (pseudo)halogen ligands, electron-withdrawing/donating/delocalising substituents on the N-ligands, and intramolecular H bonds shows that: 1) the design of platinum(IV) complexes with intense bands shifted towards longer wavelengths (from 289 to ∼330 nm) can be achieved by introducing intramolecular H bonds involving the OH ligands and 2-hydroxyquinoline or by iodido ligands; 2) mesomeric electron-withdrawing substituents on pyridine result in low-energy absorption with significant intensity in the visible region; and 3) the distinct makeup of the molecular orbitals involved in the electronic transitions for cis/trans-{Pt(N(3) )(2) } isomers results in different photoproducts. In general, the comparison of the optimised geometries shows that Pt(IV) complexes with longer PtL bonds are more likely to undergo photoreduction with longer-wavelength light. The novel complex trans,trans,trans-[Pt(N(3) )(2) (OH)(2) (NH(3) )(4-nitropyridine)] with predicted absorption in the visible region has been synthesised. The experimental UV/Vis spectrum in aqueous solution correlates well with the intense band in the computed spectrum, whereas the overlay in the low-energy region can be improved by a solvent model. This combined computational and experimental study shows that TDDFT can be used to tune the coordination environment for optimising photoactive Pt(IV) compounds as anticancer agents.
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http://dx.doi.org/10.1002/chem.201200782DOI Listing
August 2012

Trans,trans,trans-[PtIV(N3)2(OH)2(py)(NH3)]: a light-activated antitumor platinum complex that kills human cancer cells by an apoptosis-independent mechanism.

Mol Cancer Ther 2012 Sep 18;11(9):1894-904. Epub 2012 Jun 18.

Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy, University of Greifswald, Greifswald, Germany.

Photoactivatable Pt(IV) diazido complexes have unusual photobiologic properties. We show here that trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(py)(NH(3))] complex 3 is a potent photoactivated cytotoxin toward human cancer cells in culture, with an average IC(50) value in 13 cell lines of 55 ± 28 μmol/L after 30 minutes (0.12 mW/cm(2)) photoactivation with UVA, although visible light was also effective. Photoactivated complex 3 was noncross-resistant to cisplatin in 3 of 4 resistant cell lines. Cell swelling but very little blebbing was seen for HL60 cells treated with irradiated complex 3. Unlike cisplatin and etoposide, both of which cause apoptosis in HL60 cells, no apoptosis was observed for UVA-activated complex 3 by the Annexin V/propidium iodide flow cytotometry assay. Changes in the levels of the autophagic proteins LC3B-II and p62 in HL60 cells treated with UVA-activated complex 3 indicate autophagy is active during cell death. In a clonogenic assay with the SISO human cervix cancer cell line, 3 inhibited colony formation when activated by UVA irradiation. Antitumor activity of complex 3 in mice bearing xenografted OE19 esophageal carcinoma tumors was photoaugmented by visible light. Insights into the novel reaction pathways of complex 3 have been obtained from (14)N{(1)H} nuclear magnetic resonance studies, which show that photoactivation pathways can involve release of free azide in buffered solution. Density functional theory (DFT) and time-dependent DFT calculations revealed the dissociative character of singlet and triplet excited states of complex 3, which gives rise to reactive, possibly cytotoxic azidyl radicals.
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http://dx.doi.org/10.1158/1535-7163.MCT-11-0959DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521251PMC
September 2012

Combined theoretical and computational study of interstrand DNA guanine-guanine cross-linking by trans-[Pt(pyridine)2] derived from the photoactivated prodrug trans,trans,trans-[Pt(N3)2(OH)2(pyridine)2].

Inorg Chem 2012 Jun 5;51(12):6830-41. Epub 2012 Jun 5.

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

Molecular modeling and extensive experimental studies are used to study DNA distortions induced by binding platinum(II)-containing fragments derived from cisplatin and a new class of photoactive platinum anticancer drugs. The major photoproduct of the novel platinum(IV) prodrug trans,trans,trans-[Pt(N(3))(2)(OH)(2)(py)(2)] (1) contains the trans-{Pt(py)(2)}(2+) moiety. Using a tailored DNA sequence, experimental studies establish the possibility of interstrand binding of trans-{Pt(py)(2)}(2+) (P) to guanine N7 positions on each DNA strand. Ligand field molecular mechanics (LFMM) parameters for Pt-guanine interactions are then derived and validated against a range of experimental structures from the Cambridge Structural Database, published quantum mechanics (QM)/molecular mechanics (MM) structures of model Pt-DNA systems and additional density-functional theory (DFT) studies. Ligand field molecular dynamics (LFMD) simulation protocols are developed and validated using experimentally characterized bifunctional DNA adducts involving both an intra- and an interstrand cross-link of cisplatin. We then turn to the interaction of P with the DNA duplex dodecamer, d(5'-C(1)C(2)T(3)C(4)T(5)C(6)G(7)T(8)C(9)T(10)C(11)C(12)-3')·d(5'-G(13)G(14)A(15)G(16)A(17)C(18)G(19)A(20)G(21)A(22)G(23)G(24)-3') which is known to form a monofunctional adduct with cis-{Pt(NH(3))(2)(py)}. P coordinated to G(7) and G(19) is simulated giving a predicted bend toward the minor groove. This is widened at one end of the platinated site and deepened at the opposite end, while the P-DNA complex exhibits a global bend of ∼67° and an unwinding of ∼20°. Such cross-links offer possibilities for specific protein-DNA interactions and suggest possible mechanisms to explain the high potency of this photoactivated complex.
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http://dx.doi.org/10.1021/ic3005745DOI Listing
June 2012

Interactions of DNA with a new platinum(IV) azide dipyridine complex activated by UVA and visible light: relationship to toxicity in tumor cells.

Chem Res Toxicol 2012 May 28;25(5):1099-111. Epub 2012 Mar 28.

Department of Biophysics, Faculty of Science, Palacky University, 17. Listopadu 12, Olomouc, Czech Republic.

The Pt(IV) diazido complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(pyridine)(2)] (1) is unreactive in the dark but is cytotoxic when photoactivated by UVA and visible light. We have shown that 1 when photoactivated accumulates in tumor cells and binds strongly to nuclear DNA under conditions in which it is toxic to tumor cells. The nature of the DNA adducts, including conformational alterations, induced by photoactivated 1 are distinctly different from those produced in DNA by conventional cisplatin or transplatin. In addition, the observation that major DNA adducts of photoactivated 1 are able to efficiently stall RNA polymerase II more efficiently than cisplatin suggests that transcription inhibition may contribute to the cytotoxicity levels observed for photoactivated 1. Hence, DNA adducts of 1 could trigger a number of downstream cellular effects different from those triggered in cancer cells by DNA adducts of cisplatin. This might lead to the therapeutic effects that could radically improve chemotherapy by platinum complexes. The findings of the present work help to explain the different cytotoxic effects of photoactivated 1 and conventional cisplatin and thereby provide new insights into mechanisms associated with the antitumor effects of platinum complexes photoactivated by UVA and visible light.
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http://dx.doi.org/10.1021/tx300057yDOI Listing
May 2012

Probing platinum azido complexes by 14N and 15N NMR spectroscopy.

Chemistry 2011 Oct 16;17(43):12059-66. Epub 2011 Sep 16.

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

Metal azido complexes are of general interest due to their high energetic properties, and platinum azido complexes in particular because of their potential as photoactivatable anticancer prodrugs. However, azido ligands are difficult to probe by NMR spectroscopy due to the quadrupolar nature of (14)N and the lack of scalar (1)H coupling to enhance the sensitivity of the less abundant (15)N by using polarisation transfer. In this work, we report (14)N and (15)N NMR spectroscopic studies of cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))] (1) and trans,trans,trans-[Pt(N(3))(2)(OH)(2)(X)(Y)], where X=Y=NH(3) (2); X=NH(3), Y=py (3) (py=pyridine); X=Y=py (4); and selected Pt(II) precursors. These studies provide the first (15)N NMR data for azido groups in coordination complexes. We discuss one- and three-bond J((15)N,(195)Pt) couplings for azido and am(m)ine ligands. The (14)N(α) (coordinated azido nitrogen) signal in the Pt(IV) azido complexes is extremely broad (W(1/2)≈2124 Hz for 4) in comparison to other metal azido complexes, attributable to a highly asymmetrical electric field gradient at the (14)N(α) atom. Through the use of anti-ringing pulse sequences, the (14)N NMR spectra, which show resolution of the broad (14)N(α) peak, were obtained rapidly (e.g., 1.5 h for 10 mM 4). The linewidths of the (14)N(α) signals correlate with the viscosity of the solvent. For (15) N-enriched samples, it is possible to detect azido (15)N resonances directly, which will allow photoreactions to be followed by 1D (15)N NMR spectroscopy. The T(1) relaxation times for 3 and 4 were in the range 5.7-120 s for (15)N, and 0.9-11.3 ms for (14)N. Analysis of the (1)J((15)N,(195)Pt) coupling constants suggests that an azido ligand has a moderately strong trans influence in octahedral Pt(IV) complexes, within the series 2-pic
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http://dx.doi.org/10.1002/chem.201101409DOI Listing
October 2011

A potent trans-diimine platinum anticancer complex photoactivated by visible light.

Angew Chem Int Ed Engl 2010 Nov;49(47):8905-8

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

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http://dx.doi.org/10.1002/anie.201003399DOI Listing
November 2010

Photochemistry in photonic crystal fiber nanoreactors.

Chemistry 2010 May;16(19):5607-12

Max-Planck-Institut für die Physik des Lichts, Günther-Scharowsky-Strasse 1/Bau 24, 91058 Erlangen, Germany.

We report the use of a liquid-filled hollow-core photonic crystal fiber (PCF) as a highly controlled photochemical reactor. Hollow-core PCFs have several major advantages over conventional sample cells: the sample volume per optical path length is very small (2.8 nL cm(-1) in the fiber used), long optical path lengths are possible as a result of very low intrinsic waveguide loss, and furthermore the light travels in a diffractionless single mode with a constant transverse intensity profile. As a proof of principle, the (very low) quantum yield of the photochemical conversion of vitamin B(12), cyanocobalamin (CNCbl) to hydroxocobalamin ([H(2)OCbl](+)) in aqueous solution was measured for several pH values from 2.5 to 7.5. The dynamics of the actively induced reaction were monitored in real-time by broadband absorption spectroscopy. The PCF nanoreactor required ten thousand times less sample volume compared to conventional techniques. Furthermore, the enhanced sensitivity and optical pump intensity implied that even systems with very small quantum yields can be measured very quickly--in our experiments one thousand times faster than in a conventional cuvette.
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http://dx.doi.org/10.1002/chem.201000496DOI Listing
May 2010

Photoactivated chemotherapy (PACT): the potential of excited-state d-block metals in medicine.

Dalton Trans 2009 Dec 11(48):10690-701. Epub 2009 Nov 11.

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

The fields of phototherapy and of inorganic chemotherapy both have long histories. Inorganic photoactivated chemotherapy (PACT) offers both temporal and spatial control over drug activation and has remarkable potential for the treatment of cancer. Following photoexcitation, a number of different decay pathways (both photophysical and photochemical) are available to a metal complex. These pathways can result in radiative energy release, loss of ligands or transfer of energy to another species, such as triplet oxygen. We discuss the features which need to be considered when developing a metal-based anticancer drug, and the common mechanisms by which the current complexes are believed to operate. We then provide a comprehensive overview of PACT developments for complexes of the different d-block metals for the treatment of cancer, detailing the more established areas concerning Ti, V, Cr, Mn, Re, Fe, Ru, Os, Co, Rh, Pt, and Cu and also highlighting areas where there is potential for greater exploration. Nanoparticles (Ag, Au) and quantum dots (Cd) are also discussed for their photothermal destructive potential. We also discuss the potential held in particular by mixed-metal systems and Ru complexes.
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http://dx.doi.org/10.1039/b917753aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933824PMC
December 2009

Photocytotoxic trans-diam(m)ine platinum(IV) diazido complexes more potent than their cis isomers.

Chem Res Toxicol 2010 Feb;23(2):413-21

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

The photocytotoxicity of a series of anticancer trans-dihydroxido [Pt(N(3))(2)(OH)(2)(NH(3))(X)] (X = alkyl or aryl amine) platinum(IV) diazido complexes has been examined, and the influence of cis-trans isomerism has been investigated. A series of photoactivatable Pt(IV)-azido complexes has been synthesized: The synthesis, characterization, and photocytotoxicity of six mixed-ligand ammine/amine Pt(IV) diazido complexes, cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))(X)] where X = propylamine (4c), butylamine (5c), or pentylamine (6c) and aromatic complexes where X = pyridine (7c), 2-methylpyridine (8c), or 3-methylpyridine (9c) are reported. Six all-trans isomers have also been studied where X = methylamine (2t), ethylamine (3t), 2-methylpyridine (8t), 4-methylpyridine (10t), 3-methylpyridine (9t), and 2-bromo-3-methylpyridine (11t). All of the complexes exhibit intense azide-to-Pt(IV) LMCT bands (ca. 290 nm for trans and ca. 260 nm for cis). When irradiated with UVA light (365 nm), the Pt(IV) complexes undergo photoreduction to Pt(II) species, as monitored by UV-vis spectroscopy. The trans isomers of complexes containing aliphatic or aromatic amines were more photocytotoxic than their cis isomers. One of the cis complexes (9c) was nonphotocytotoxic despite undergoing photoreduction. Substitution of NH(3) ligands by MeNH(2) or EtNH(2) results in more potent photocytotoxicity for the all-trans complexes. The complexes were all nontoxic toward human keratinocytes (HaCaT) and A2780 human ovarian cancer cells in the dark, apart from the 3-methylpyridine (9t), 2-bromo-3-methylpyridine (11t), and 4-methylpyridine (10t) derivatives.
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http://dx.doi.org/10.1021/tx900372pDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933822PMC
February 2010

Synthesis, characterisation and photochemistry of Pt(IV) pyridyl azido acetato complexes.

Dalton Trans 2009 Apr 24(13):2315-25. Epub 2009 Feb 24.

School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh, UKEH9 3JJ.

Pt(II) azido complexes [Pt(bpy)(N(3))(2)] (1), [Pt(phen)(N(3))(2)] (2) and trans-[Pt(N(3))(2)(py)(2)] (3) incorporating the bidentate diimine ligands 2,2'-bipyridine (bpy), 1,10-phenanthroline (phen) or the monodentate pyridine (py) respectively, have been synthesised from their chlorido precursors and characterised by X-ray crystallography; complex 3 shows significant deviation from square-planar geometry (N(3)-Pt-N(3) angle 146.7 degrees ) as a result of steric congestion at the Pt centre. The novel Pt(IV) complexes trans, cis-[Pt(bpy)(OAc)(2)(N(3))(2)] (), trans, cis-[Pt(phen)(OAc)(2)(N(3))(2)] (), trans, trans, trans-[Pt(OAc)(2)(N(3))(2)(py)(2)] (), were obtained from via oxidation with H(2)O(2) in acetic acid followed by reaction of the intermediate with acetic anhydride. Complexes 4-6 exhibit interesting structural and photochemical properties that were studied by X-ray, NMR and UV-vis spectroscopy and TD-DFT (time-dependent density functional theory). These Pt(IV) complexes exhibit greater absorption at longer wavelengths (epsilon = 9756 M(-1) cm(-1) at 315 nm for 4 ; epsilon = 796 M(-1) cm(-1) at 352 nm for 5 ; epsilon = 16900 M(-1) cm(-1) at 307 nm for 6 , in aqueous solution) than previously reported Pt(IV) azide complexes, due to the presence of aromatic amines, and 4-6 undergo photoactivation with both UVA (365 nm) and visible green light (514 nm). The UV-vis spectra of complexes 4-6 were calculated using TD-DFT; the nature of the transitions contributing to the UV-vis bands provide insight into the mechanism of production of the observed photoproducts. The UV-vis spectra of 1-3 were also simulated by computational methods and comparison between Pt(II) and Pt(IV) electronic and structural properties allowed further elucidation of the photochemistry of 4-6.
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http://dx.doi.org/10.1039/b820550gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2933821PMC
April 2009

Proton sponge phosphines: electrospray-active ligands.

Dalton Trans 2006 Oct 24(38):4570-9. Epub 2006 Aug 24.

Department of Chemistry, The University of Cambridge, Lensfield Road, Cambridge, UKCB2 1EW.

Attachment of a proton sponge to a phosphine ligand renders neutral complexes of the ligand highly amenable to analysis by electrospray ionisation mass spectrometry (ESI-MS). The ligand 1,8-bis(dimethylamino)naphthyldiphenylphosphine (3) is extremely efficient and highly selective in forming exclusively [M + H]+ ions, which may be detected at very low concentration. Ionisation efficiency of 3 in the presence of H+ approached 100%. The bis-substituted ligand bis{1,8-bis(dimethylamino)naphthyl}phenylphosphine (4) was also prepared and characterised, as were Fe(CO)4- (5c), Mn(eta5-C5H4Me)(CO)2- (6) and W(CO)5- (7) complexes of 3. Compounds 3, 3.HBr.EtOH, 4 and 5c were all structurally characterised.
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http://dx.doi.org/10.1039/b609561eDOI Listing
October 2006
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