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

Journal article

Complexes trans,trans,trans-[Pt(N-3)(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)(N-3)(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 mu M) and complex 2 was particularly active towards the cisplatin-resistant cell line A2780cis (IC50 3.7 mu M). Unlike 4, complexes 1-3 were phototoxic under green light irradiation (517 nm), with minimal toxicity in the dark. A pK(a)(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.NF thanks the Wellcome Trust (201406/Z/16/Z); Cancer Research UK (CR-UK) grant number C5255/A18085 through the Cancer Research UK Oxford Centre and the John Fell Fund for funding. NF thanks Profs. Stephen Faulkner for support. PJS and NF thank the EPSRC (for grant EP/P030572/1 and studentship for ES), PJS also thanks the ERC (grant 247450). L. S. performed this work under the Severo Ochoa Centres of Excellence Programme run by the Spanish State Research Agency, grant no. CEX2018-000867-S (DIPC). L. S. also thanks the Spanish Multi-MetDrugs network (RED2018-102471-T) for fruitful discussio

Authors: Shaili, E; Romero, MJ; Salassa, L; Woods, JA; Butler, JS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Royal Society of Chemistry
• Journal: Dalton Transactions
• Volume: 50
• Issue: 30
• Pages: 10593-10607
• Publication date: 2021-08-04
• DOI: 10.1039/d1dt01730f
• EISSN: 1477-9234
• ISSN: 1477-9226
• Language: English
• Keywords: Electron paramagnetic resonance; Organic chemistry; Phototoxicity; Spectroscopy; Carboxylate; Visible spectrum; Nuclear magnetic resonance; Medicinal chemistry; Irradiation; Pyridine; Stereochemistry; Catalysis; Platinum; Photochemistry; Crystallography; Materials science; Chemistry