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Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

ABSTRACT: 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.

SUBMITTER: Shaili E

PROVIDER: S-EPMC8335519 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

Shaili Evyenia E Romero Marίa J MJ Salassa Luca L Woods Julie A JA Butler Jennifer S JS Romero-Canelón Isolda I Clarkson Guy G Habtemariam Abraha A Sadler Peter J PJ Farrer Nicola J NJ

Dalton transactions (Cambridge, England : 2003) 20210801 30

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 dis ...[more]

PMID: 34278398

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Project description: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.

Dataset Information

Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

Publications

Platinum(IV)-azido monocarboxylato complexes are photocytotoxic under irradiation with visible light.

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