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

Yao Zhao, Julie A. Woods, Nicola J. Farrer, Kim S. Robinson, Jitka Pracharova, Jana Kasparkova, Olga Novakova, Huilin Li, Luca Salassa, Ana M. Pizarro, Guy J. Clarkson, Lijiang Song, Viktor Brabec, Peter J. Sadler

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    Abstract

    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 1?p and 1?q. 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.
    Original languageEnglish
    Pages (from-to)9578-9591
    Number of pages14
    JournalChemistry: a European Journal
    Volume19
    Issue number29
    DOIs
    Publication statusPublished - 15 Jul 2013

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    DNA Adducts
    Platinum
    Amines
    DNA
    Cisplatin
    Cells
    HMGB1 Protein
    Photodissociation
    Thiazoles
    Thymus
    Prodrugs
    Polymorphism
    Discrete Fourier transforms
    Oligonucleotides
    Pharmaceutical Preparations
    Glutathione
    Hydrolysis
    Assays
    Plasmids
    Nucleotides

    Cite this

    Zhao, Y., Woods, J. A., Farrer, N. J., Robinson, K. S., Pracharova, J., Kasparkova, J., ... Sadler, P. J. (2013). Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts. Chemistry: a European Journal, 19(29), 9578-9591. https://doi.org/10.1002/chem.201300374
    Zhao, Yao ; Woods, Julie A. ; Farrer, Nicola J. ; Robinson, Kim S. ; Pracharova, Jitka ; Kasparkova, Jana ; Novakova, Olga ; Li, Huilin ; Salassa, Luca ; Pizarro, Ana M. ; Clarkson, Guy J. ; Song, Lijiang ; Brabec, Viktor ; Sadler, Peter J. / Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts. In: Chemistry: a European Journal. 2013 ; Vol. 19, No. 29. pp. 9578-9591.
    @article{56fa89afd1384120848cb063bbdd969b,
    title = "Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts",
    abstract = "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 1?p and 1?q. 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.",
    author = "Yao Zhao and Woods, {Julie A.} and Farrer, {Nicola J.} and Robinson, {Kim S.} and Jitka Pracharova and Jana Kasparkova and Olga Novakova and Huilin Li and Luca Salassa and Pizarro, {Ana M.} and Clarkson, {Guy J.} and Lijiang Song and Viktor Brabec and Sadler, {Peter J.}",
    note = "Copyright {\circledC} 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",
    year = "2013",
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    day = "15",
    doi = "10.1002/chem.201300374",
    language = "English",
    volume = "19",
    pages = "9578--9591",
    journal = "Chemistry: a European Journal",
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    Zhao, Y, Woods, JA, Farrer, NJ, Robinson, KS, Pracharova, J, Kasparkova, J, Novakova, O, Li, H, Salassa, L, Pizarro, AM, Clarkson, GJ, Song, L, Brabec, V & Sadler, PJ 2013, 'Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts', Chemistry: a European Journal, vol. 19, no. 29, pp. 9578-9591. https://doi.org/10.1002/chem.201300374

    Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts. / Zhao, Yao; Woods, Julie A.; Farrer, Nicola J.; Robinson, Kim S.; Pracharova, Jitka; Kasparkova, Jana; Novakova, Olga; Li, Huilin; Salassa, Luca; Pizarro, Ana M.; Clarkson, Guy J.; Song, Lijiang; Brabec, Viktor; Sadler, Peter J.

    In: Chemistry: a European Journal, Vol. 19, No. 29, 15.07.2013, p. 9578-9591.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts

    AU - Zhao, Yao

    AU - Woods, Julie A.

    AU - Farrer, Nicola J.

    AU - Robinson, Kim S.

    AU - Pracharova, Jitka

    AU - Kasparkova, Jana

    AU - Novakova, Olga

    AU - Li, Huilin

    AU - Salassa, Luca

    AU - Pizarro, Ana M.

    AU - Clarkson, Guy J.

    AU - Song, Lijiang

    AU - Brabec, Viktor

    AU - Sadler, Peter J.

    N1 - Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

    PY - 2013/7/15

    Y1 - 2013/7/15

    N2 - 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 1?p and 1?q. 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.

    AB - 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 1?p and 1?q. 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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    DO - 10.1002/chem.201300374

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    SP - 9578

    EP - 9591

    JO - Chemistry: a European Journal

    JF - Chemistry: a European Journal

    SN - 0947-6539

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