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Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts
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Zhao, Yao, (Researcher in chemistry), 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, V. (Viktor) and Sadler, P. J. (2013) Diazido mixed-amine platinum(IV) anticancer complexes activatable by visible-light form novel DNA adducts. Chemistry - A European Journal, Volume 19 (Number 29). pp. 9578-9591. doi:10.1002/chem.201300374 ISSN 0947-6539.
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Official URL: http://dx.doi.org/10.1002/chem.201300374
Abstract
Platinum diam(m)ine complexes, such as cisplatin, are successful anticancer drugs, but suffer from problems of resistance and side-effects. Photoactivatable PtIV 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 PtII 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.
| Item Type: | Journal Article | ||||||||
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| Subjects: | R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer) | ||||||||
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||||
| Library of Congress Subject Headings (LCSH): | Antineoplastic agents, Platinum -- Therapeutic use | ||||||||
| Journal or Publication Title: | Chemistry - A European Journal | ||||||||
| Publisher: | Wiley - V C H Verlag GmbH & Co. KGaA | ||||||||
| ISSN: | 0947-6539 | ||||||||
| Official Date: | 8 July 2013 | ||||||||
| Dates: |
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| Volume: | Volume 19 | ||||||||
| Number: | Number 29 | ||||||||
| Number of Pages: | 14 | ||||||||
| Page Range: | pp. 9578-9591 | ||||||||
| DOI: | 10.1002/chem.201300374 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||
| Date of first compliant deposit: | 25 December 2015 | ||||||||
| Date of first compliant Open Access: | 25 December 2015 | ||||||||
| Funder: | University of Warwick Postgraduate Research Scholarship, Engineering and Physical Sciences Research Council (EPSRC), European Research Council (ERC), Marie Curie Intra-European Fellowship (IEF), Science City Research Alliance, Advantage West Midlands (AWM), European Regional Development Fund (ERDF), Czech Science Foundation (CSF), Akademie věd České republiky [Academy of Sciences of the Czech Republic], Univerzita Palackého v Olomouci [Palacky University], Czech Republic. Ministerstvo školství, mládeže a tělovýchovy [Ministry of Education, Youth, and Sport] | ||||||||
| Grant number: | EP/ G006792/1 (EPSRC), 247450 (ERC), 220281 (IEF), 301/10/0598 (CSF), M200041201 (AvCr), PrF-2012- 026 (UPvO), CZ-1.07/ 2.3.00/20.0057 (CR.MS,MT) |
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