Abstract
A series of trans-di-(N-heterocyclic)imine dihydroxido diazido PtIV complexes of the form trans,trans,trans-[Pt(N3)2(OH)2(L1)(L2)] where L = pyridine, 2-picoline, 3-picoline, 4-picoline, thiazole and 1-methylimidazole have been synthesised and characterised, and their photochemical and photobiological activity evaluated. Notably, complexes 19 (L1 = py, L2 = 3-pic) and 26 (L1 = L2 = 4-pic) were potently phototoxic following irradiation with visible light (420 nm), with IC50 values of 4.0 μM and 2.1 μM respectively (A2780 cancer cell line), demonstrating greater potency than the previously reported complex 1 (L1 = L2 = py; 6.7 μM); whilst also being minimally toxic in the absence of irradiation. Complexes with mixed N-(heterocyclic)imine ligands 19 and 20 (L1 = py, L2 = 4-pic) were particularly photocytotoxic towards cisplatin resistant (A2780cis) cell lines. Complex 18 (L1 = py, L2 = 2-pic) was comparatively less photocytotoxic (IC50 value 14.5 μM) than the other complexes, despite demonstrating the greatest absorbance at the irradiation wavelength and the fastest half-life for loss of the N3 → Pt LMCT transition upon irradiation (λ irr = 463 nm) in aqueous solution. Complex 29 (X1 = X2 = thiazole) although potently phototoxic (2.4 μM), was also toxic towards cells in the absence of irradiation.
Highlights
For cancers treated with chemotherapy, approximately half of patients currently receive a platinum(II) drug, typically in combination with other therapies.1,2 The widely-used platinum(II) complexes cisplatin,3 carboplatin4 and oxaliplatin5,6 all include ammine or aliphatic amine ligands, and exhibit potent activity against a number of different cancers
Picoplatin was developed to tackle the problem of platinum drug deactivation by S-donor molecules, such as glutathione, which can lead to the development of resistance
The steric hindrance caused by the methyl substituent on the pyridyl ring in close proximity to the Pt centre is thought to reduce the rates of side-reactions which can diminish drug potency
Summary
For cancers treated with chemotherapy, approximately half of patients currently receive a platinum(II) drug, typically in combination with other therapies. The widely-used platinum(II) complexes cisplatin, carboplatin and oxaliplatin all include ammine or aliphatic amine ligands, and exhibit potent activity against a number of different cancers. In addition to the ligands themselves, the use of aromatic pyridine-like ligands or substituted amines in a trans rather than a cis geometry in a Pt complex can give rise to cytotoxic activity in cisplatin-resistant cell lines.12,13 Trans complexes such as trans-[PtCl2(NH3)(thiazole)] (Fig. 1C) which include non-pyridyl heterocyclic amines such thiazole demonstrate a good combination of cytotoxicity, aqueous solubility and in vivo activity, and trans-[PtCl2(4pic)(piperazine$H)]+ (Fig. 1D) which incorporates picolyl and piperazine ligands is highly cytotoxic towards cancer cells, with a mechanism of action distinct from cisplatin.. Trans complexes such as trans-[PtCl2(NH3)(thiazole)] (Fig. 1C) which include non-pyridyl heterocyclic amines such thiazole demonstrate a good combination of cytotoxicity, aqueous solubility and in vivo activity, and trans-[PtCl2(4pic)(piperazine$H)]+ (Fig. 1D) which incorporates picolyl and piperazine ligands is highly cytotoxic towards cancer cells, with a mechanism of action distinct from cisplatin.15 Another strategy in the development of more selective anticancer drugs is the use of PtIV prodrugs; oxidation of squareplanar PtII complexes to octahedral PtIV complexes incorporates two additional ligands into the axial positions. We present the synthesis, characterisation, photochemical and photobiological evaluation of a series of novel trans-di-(N-heterocyclic)imine dihydroxido diazido PtIV complexes (Fig. 2)
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