Design, synthesis, characterisation and chemical reactivity of mixed-ligand platinum(ii) oxadiazoline complexes with potential cytotoxic properties

Abstract

A series of mixed ligand platinum(II) oxadiazoline complexes bearing 7-nitro-1,3,5-triazaadamantane (7-NO(2)TAA) as a labile and reactive nitrogen ligand has been synthesised from easily accessible starting materials. [2+3] cycloaddition of nitrones R(1)R(2)C-N(+)(Me)O(-) to only one of the nitrile ligands in trans-[PtX(2)(PhCN)(2)] (X = Cl, Br) results in the selective formation of mono-oxadiazoline complexes trans-[PtX(2)(PhCN){N=C(Ph)-O-N(Me)-CR(1)R(2)}] from which the remaining nitrile can be replaced by 7-NO(2)TAA. The resulting complexes trans-[PtX(2)(7-NO(2)TAA) {N=C(Ph)-O-N(Me)-CR(1)R(2)}] and their precursors were characterised by elemental analysis, IR and multinuclear NMR spectroscopy.The suitability of the target complexes as anticancer agents was extrapolated from their general chemical reactivity. They are stable in DMSO, but react with thiols and undergo aquation of a chloro ligand. In the absence of a competing ligand, the coordinated 7-NO(2)TAA ligand slowly hydrolyses in an aqueous medium under release of formaldehyde, and this could induce bioactivity independent of the one typically found with platinum compounds. With nitrogen heterocycles such as pyridine a slow exchange of the 7-NO(2)TAA ligand occurs. A combined DFT/AIM study confirms the reaction observed in the experiment and predicts that other nitrogen heterocycles such as DNA nucleobases should react in the same way. Moreover, the 7-NO(2)TAA should be even more labile in an aqueous medium where protonation of the remaining amines can occur. A PM6 molecular modelling study suggests that the PtCl(oxadiazoline) fragment formed after release of one chloro and the labile 7-NO(2)TAA ligand fits well into the DNA groove and is able to form d(GpG) intrastrand crosslinks similar to the ones observed with cisplatin.

Mononuclear Transition Metal Complexes of 7‐Nitro‐1,3,5‐Triazaadamantane

“…[17] Also the moderately soluble intermediate in the reaction, [PtCl2(PhCN)(NO2-TAA)], displays a very similar 13 C spectrum for the NO2-TAA moiety. 6 and 7 could not be analysed in solution due to the poor solubility in all common NMR solvents.…”

“…in the form of cytotoxic Pt compounds where a certain degree of ligand lability is desired. This has recently been proposed [17] and a number of mixed ligand Pt(II) complexes with NO2-TAA have been synthesised. [18] These complexes are more cytotoxic in in-vitro experiments than structurally related platinum complexes that do not bear the NO2-TAA moiety.…”

“…Stoichiometry control allows for the selective synthesis of mononuclear compounds where NO2-TAA binds in a monodentate manner. However, the corresponding dinuclear species were obtained as by-products or when two equivalents of the Pt(II) precursor were used, [17] suggesting that the bidentate binding mode might be preferred. In this aspect, NO2-TAA closely resembles the behaviour of hmta as a ligand.…”

Interaction of metal complexes with nucleic acids

“…1a) 8 and dimethyl sulfoxide with a pyridine ring attached via a benzyl spacer to a copper(II) complex 2. 9 In the latter, the copper moiety is employed as an artificial metallonuclease; incorporation of the platinum centre allows stronger binding with DNA (via coordination) thereby improving cleavage efficiency.…”

Synthesis, characterisation and in vitro cytotoxicity of mixed ligand Pt(ii) oxadiazoline complexes with hexamethylenetetramine and 7-nitro-1,3,5-triazaadamantane

“…sulfoxide), 13 or by mono-cycloaddition to only one of two initially equivalent nitriles 14 and subsequent ligand exchange. 11 The latter method lead to complexes bearing a reactive and labile NO2-TAA ligand, 15 designed to achieve some selectivity in cellular uptake and enhanced reactivity in tumour cells with fairly simple means. The non-coordinated nitrogen atoms are expected to partially protonate in an aqueous medium, to give cationic complexes that are more prone to penetrate the cell membrane.…”