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

Evyenia Shaili,Julie A Woods,Luca Salassa,Marίa J Romero,Isolda Romero-Canelón,Nicola J Farrer,Peter J Sadler,Guy Clarkson,Abraha Habtemariam,Jennifer S Butler

doi:10.1039/d1dt01730f

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.

Highlights

40% of the cancer patients treated with chemotherapy receive a platinum(II)-based medicine such as cisplatin, carboplatin or oxaliplatin.[1]
Precursor compounds N-methylisatoic acid (N-MIA) (5), trans[PtCl2( py)2] (6), trans-[Pt(N3)2( py)2] (7) and complex 4 were synthesized as reported previously; characterisation was consistent with previous reports.[29]
Photoactivation studies comparing complexes 1–3 to their dihydroxido synthetic precursor trans,trans,trans-[Pt(N3)2(OH)2( py)2] 4 indicate a 3-fold faster rate of photodegradation for 1–3 through monitoring loss of the ligand–to–metal chargetransfer (LMCT) band in the UV-vis absorbance spectrum when irradiated with green light (517 nm)

Summary

Introduction

40% of the cancer patients treated with chemotherapy receive a platinum(II)-based medicine such as cisplatin, carboplatin or oxaliplatin.[1] Despite the wide-spread use of platinum-based drugs2 – in combination therapies – disadvantages exist, including the development of resistance and serious side-effects of treatment.[3] Octahedral, Pt(IV) prodrugs with a d6 electronic configuration typically demonstrate greater kinetic inertness than Pt(II) complexes, as well as offering additional ligand sites for derivation.[4]. Pt(IV) prodrugs are classically regarded to exert their cytotoxic effect following reduction to Pt(II) species in vivo, Pt(IV) complexes may form adducts with biomolecules.[5] Photoactivated chemotherapy (PACT) provides both spatial and temporal control over Pt(IV) prodrug reduction. Photoreduction of Pt(IV) prodrugs of carboplatin,[6] oxaliplatin[7] and cisplatin8 – either by direct irradiation of the Pt(IV) complex, or by employing separate photosensitisers – have been reported.

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