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Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)]

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Westendorf, Aron, Zerzankova, Lenka, Salassa, Luca, Sadler, P. J., Brabec, Viktor and Bednarski, Patrick J.. (2011) Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)]. Journal of Inorganic Biochemistry, Vol.105 (No.5). pp. 652-662. ISSN 01620134

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Official URL: http://dx.doi.org/10.1016/j.jinorgbio.2011.01.003

Abstract

The photocytotoxicity and photobiochemical properties of the new complex trans, trans, trans-[Pt(N3)2(OH)2(NH3)(piperidine)] (5) are compared with its analogue containing the less basic and less lipophilic ligand pyridine (4). The log P (n-octanol/water) values were of -1.16 and -1.84 for the piperidine and pyridine complexes, respectively, confirmed that piperidine increases the hydrophobicity of the complex. DFT and TDDFT calculations indicate that 5 has accessible singlet and triplet states which can promote ligand dissociation when populated by both UVA and visible white light. When activated by UVA or white light, both compounds showed similar cytotoxic potencies in various human cancer cell lines although their selectivity was different. The time needed to reach similar antiproliferative activity was noticeably decreased by introducing the piperidine ligand. Neither compound showed cross-resistance in three oxoplatin-resistant cell lines. Furthermore, both compounds showed similar anticlonogenic activity when activated by UVA radiation. Interactions of the light-activated complexes with DNA showed similar kinetics and levels of DNA platination and similar levels of DNA interstrand cross-linking (ca. 5 %). Also the ability to unwind double stranded DNA where comparable for the piperidine analogue (24°, respectively), while the piperidine complex showed higher potency in changing the conformation of DNA, as measured in an ethidium bromide binding assay. These results indicate that the nature of the heterocyclic nitrogen ligand can have subtle influences on both the phototoxicity and photobiochemistry of this class of photochemotherapeutic agents.

Item Type:	Journal Article
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Science > Chemistry
Library of Congress Subject Headings (LCSH):	Piperidine -- Analysis, Pyridine -- Analysis, Photobiochemistry, Antineoplastic agents
Journal or Publication Title:	Journal of Inorganic Biochemistry
Publisher:	Elsevier Science BV
ISSN:	01620134
Date:	May 2011
Volume:	Vol.105
Number:	No.5
Page Range:	pp. 652-662
Identification Number:	10.1016/j.jinorgbio.2011.01.003
Status:	Peer Reviewed
Access rights to Published version:	Restricted or Subscription Access
Funder:	Seventh Framework Programme (European Commission) (FP7/2007-2013), European Research Council (ERC), European Union (EU)
Grant number:	220281 (FP7), 247450 (ERC)
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URI:	http://wrap.warwick.ac.uk/id/eprint/36963