Structure and dynamics of a platinum(II) aminophosphine complex and its nucleobase adducts

Abstract

The anti-cancer aminophosphine complex, cis-[Pt(Me₂N(CH₂)₂PPh₂-N,P)Cl(Me₂N(CH₂)₂PPh₂-P)]Cl, 1, is shown, by ¹H and ³¹P NMR studies, to undergo reversible chelate ring-closing and -opening in aqueous solution. The rate for this process (21 ± 2 s⁻¹ at pH* 8.5, 295 K), which is slow on the NMR timescale, varies significantly with pH values, chloride ion concentration and temperature. The chelate-ring-opened form is favoured at acidic pH values. The activation parameters which govern this process, have been determined via³¹P-2-D EXSY NMR spectroscopy, and the mechanism of chelate ring-opening is discussed. The X-ray crystal structure of the ring-opened complex, cis-[Pt(Me₂N(CH₂)₂PPh₂-N,P)Cl(Me₂NH(CH₂)₂PPh₂-P)](NO₃)₂·1.5H₂O, 1a, shows that the Pt–N bond is relatively long (2.147 Å). The nucleotide 5′-guanosine monophosphate (5′-GMP) binds via N7 and displaces the Cl ligand. Unusually for a platinum(II) amine complex, GMP binding is rapid and reversible. Two isomeric GMP adducts are formed in a 3∶1 ratio below pH* 6 (pH meter reading in D₂O). Above pH* 8.2, the predominant species are non N7-bound adducts. The on-rate for 5′-GMP binding to the ring-closed form cis-[Pt(Me₂N(CH₂)₂PPh₂-N,P)₂]²⁺, complex 2, to give the major adduct (pH* 8.5, 298 K) is 0.20 s⁻¹ and the off-rate is 0.018 s⁻¹. The 5′-GMP adducts were modelled by molecular mechanics calculations. These revealed possible hydrogen bonding between the dangling arm amino group and the 5′-phosphate. Supporting evidence for this came from solution studies with other GMP derivatives (3′, 5′-cyclic GMP, 3′-GMP and 9-ethylguanine). Our findings are discussed in terms of potential new methods for drug delivery and new approaches to drug design.