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 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.
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, CV4 7AL, UK.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Julie A
authors.initials: JA
authors.lastname: Woods
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Farrer
authors.forename: Kim S
authors.initials: KS
authors.lastname: Robinson
authors.forename: Jitka
authors.initials: J
authors.lastname: Pracharova
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Olga
authors.initials: O
authors.lastname: Novakova
authors.forename: Huilin
authors.initials: H
authors.lastname: Li
authors.forename: Luca
authors.initials: L
authors.lastname: Salassa
authors.forename: Ana M
authors.initials: AM
authors.lastname: Pizarro
authors.forename: Guy J
authors.initials: GJ
authors.lastname: Clarkson
authors.forename: Lijiang
authors.initials: L
authors.lastname: Song
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Sadler
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001386:Azides / Q000737:chemistry* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004247:DNA / Q000737:chemistry*; D018736:DNA Adducts / Q000737:chemistry*; D006801:Humans; D008027:Light; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D001386:Azides; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D011355:Prodrugs; D011725:Pyridines; C034697:transplatin; D010984:Platinum; D004247:DNA; C427203:calf thymus DNA; D002945:Cisplatin
keywords: DNA binding; antitumor agents; medicinal chemistry; photoactivity; platinum