Publications by authors named "Evyenia Shaili"

10 Publications

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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

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

Photoactivatable platinum anticancer complex can generate tryptophan radicals.

Chem Commun (Camb) 2018 Dec;54(98):13845-13848

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

l-Tryptophan (Trp), melatonin (MLT) and the Trp-peptide pentagastrin quenched the formation of azidyl radicals generated on irradiation of the anticancer complex trans,trans,trans-[Pt(pyridine)2(N3)2(OH)2] with visible light, giving rise to C3-centred indole radicals which were characterized for Trp and MLT using an EPR spin-trap; indole, together with azidyl and hydroxyl radicals, have potential roles in a multitargeting mechanism of action against resistant cancers.
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http://dx.doi.org/10.1039/c8cc06496bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336088PMC
December 2018

Sequence-dependent attack on peptides by photoactivated platinum anticancer complexes.

Chem Sci 2018 Mar 12;9(10):2733-2739. Epub 2018 Feb 12.

Department of Chemistry , University of Warwick , Gibbet Hill Road , Coventry CV4 7AL , UK . Email: ; Email: ; ; Fax: +44 (0)24 765 23819 ; Tel: +44 (0)24 76151008 ; Tel: +44 (0)24 765 23818.

Octahedral platinum(iv) complexes such as ,,-[Pt(N)(OH)(pyridine)] () are stable in the dark, but potently cytotoxic to a range of cancer cells when activated by UVA or visible light, and active . Photoactivation causes the reduction of the complex and leads to the formation of unusual Pt(ii) lesions on DNA. However, radicals are also generated in the excited state resulting from photoactivation (J. S. Butler, J. A. Woods, N. J. Farrer, M. E. Newton and P. J. Sadler, , 2012, , 16508-16511). Here we show that once photoactivated, also can interact with peptides, and therefore proteins are potential targets of this candidate drug. High resolution FT-ICR MS studies show that reactions of activated by visible light with two neuropeptides Substance P, RPKPQQFFGLM-NH () and [Lys]-Bombesin, pEQKLGNQWAVGHLM-NH () give rise to unexpected products, in the form of both oxidised and platinated peptides. Further MS/MS analysis using electron-capture dissociation (ECD) dissociation pathways (enabling retention of the Pt complex during fragmentation), and EPR experiments using the spin-trap DEPMPO, show that the products generated during the photoactivation of depend on the amino acid composition of the peptide. This work reveals the multi-targeting nature of excited state platinum anticancer complexes. Not only can they target DNA, but also peptides (and proteins) by sequence dependent platination and radical mechanisms.
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http://dx.doi.org/10.1039/c7sc05135bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5911824PMC
March 2018

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

Nonclinical data supporting orphan medicinal product designations: lessons from rare neurological conditions.

Drug Discov Today 2018 01 4;23(1):26-48. Epub 2017 Oct 4.

Committee of Orphan Medicinal Products, European Medicines Agency, London, UK; Universidade de Lisboa, Faculdade de Farmácia, Lisbon, Portugal.

Here, we provide an in-depth literature and experience-based review of nonclinical models and data used to support orphan medicinal product designations (OMPDs) in rare neurodegenerative conditions. The Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency updates its assessment processes based on scientific progress and aims to provide transparent criteria required in support of OMPDs. Thus, we also provide an updated analysis of existing nonclinical models in selected conditions and identify key features of nonclinical studies that are crucial for the support of OMPDs. This could not only inform future drug development in rare neurological conditions, but also indicate areas where the use of nonclinical models can be made more efficient.
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http://dx.doi.org/10.1016/j.drudis.2017.09.015DOI Listing
January 2018

Comprehensive Vibrational Spectroscopic Investigation of trans,trans,trans-[Pt(N3)2(OH)2(py)2], a Pt(IV) Diazido Anticancer Prodrug Candidate.

Inorg Chem 2016 Jun 3;55(12):5983-92. Epub 2016 Jun 3.

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

We report a detailed study of a promising photoactivatable metal-based anticancer prodrug candidate, trans,trans,trans-[Pt(N3)2(OH)2(py)2] (C1; py = pyridine), using vibrational spectroscopic techniques. Attenuated total reflection Fourier transform infrared (ATR-FTIR), Raman, and synchrotron radiation far-IR (SR-FIR) spectroscopies were applied to obtain highly resolved ligand and Pt-ligand vibrations for C1 and its precursors (trans-[Pt(N3)2(py)2] (C2) and trans-[PtCl2(py)2] (C3)). Distinct IR- and Raman-active vibrational modes were assigned with the aid of density functional theory calculations, and trends in the frequency shifts as a function of changing Pt coordination environment were determined and detailed for the first time. The data provide the ligand and Pt-ligand (azide, hydroxide, pyridine) vibrational signatures for C1 in the mid- and far-IR region, which will provide a basis for the better understanding of the interaction of C1 with biomolecules.
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http://dx.doi.org/10.1021/acs.inorgchem.6b00476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916484PMC
June 2016

A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin.

Chemistry 2015 Dec 2;21(50):18474-86. Epub 2015 Nov 2.

Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028, Barcelona (Spain).

A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.
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http://dx.doi.org/10.1002/chem.201502373DOI Listing
December 2015

An integrin-targeted photoactivatable Pt(IV) complex as a selective anticancer pro-drug: synthesis and photoactivation studies.

Chem Commun (Camb) 2015 Jun;51(44):9169-72

Departament de Química Orgànica and IBUB, Universitat de Barcelona, Barcelona, E-08028, Spain.

A new anticancer agent based on the conjugation of a photoactivatable Pt(IV) pro-drug to a cyclic RGD-containing peptide is described. Upon visible light irradiation, phototoxicity was induced preferentially in SK-MEL-28 melanoma cancer cells overexpressing αVβ3 integrin compared to control DU-145 human prostate carcinoma cells.
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http://dx.doi.org/10.1039/c5cc03180jDOI Listing
June 2015

Platinum anticancer drugs and photochemotherapeutic agents: recent advances and future developments.

Authors:
Evyenia Shaili

Sci Prog 2014 ;97(Pt 1):20-40

Platinum-based chemotherapeutic drugs such as cisplatin, carboplatin and oxaliplatin are widely applied for the treatment of various types of tumours. Over the last few decades, a large variety of Pt(II) and Pt(IV) complexes have been developed to improve the applicability in a wider spectrum of cancers, increase their therapeutic window and reduce the dose-limiting side effects. Photodynamic therapy (PDT), which is the administration of a photosensitiser followed by visible light activation, is a promising route to avoid damage to healthy cells and the surrounding tissue. Transition metal complexes as photochemotherapeutic agents are an attractive option for further development in the field of photoactivated chemotherapy (PACT). These complexes exhibit different numbers and types of excited states which are easily accessible upon light irradiation, subsequently giving rise to the formation of various photoproducts that can enable a distinct mode of action. Platinum-diazido complexes are promising candidates for PACT due to the low cytotoxicity when irradiated with visible light. This review summarises the mode of action of current platinum anticancer drugs with cisplatin as a lead example and the development of non-conventional Pt(II) complexes. Background information regarding PDT the photophysical and photochemical properties of metal complexes is provided, as well as notable examples of photoactivated metal complexes with biological activity. Particular emphasis is placed on recent developments on platinum photoactivated drugs.
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http://dx.doi.org/10.3184/003685014X13904811808460DOI Listing
May 2014
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