Control of aminophosphine chelate ring-opening in Pt(ii) and Pd(ii) complexes: potential dual-mode anticancer agents

Abstract

We show that bis(aminophosphine) complexes of the type [M(R¹R²N(CH₂)_nPPh₂)₂]²⁺, M = Pt(II) or Pd(II), can exist in chelate ring-closed and ring-opened forms both in the solid state and in aqueous solution. The equilibrium between them in solution can be controlled by the nature of the groups R¹ and R² (H, Me, Bz, cyclohexyl), by the bridge length n, and by the pH and Cl⁻ concentration. X-Ray crystal structures are reported for the ring-closed complexes cis-[Pt(H₂N(CH₂)₂PPh₂-P,N)₂]Cl₂, cis-[Pt(H₂N(CH₂)₃PPh₂-P,N)₂]Cl₂, and cis-[Pt(Me(H)N(CH₂)₂PPh₂-P,N)₂][HCl₂]₂, the mono-ring-opened complex cis-[Pd(Me₂N(CH₂)₂PPh₂-N,P)Cl(Me₂NH(CH₂)₂PPh₂-P)](NO₃)₂, the di-ring-opened complex cis-[Pt(Me₂N(CH₂)₃PPh₂-P)₂Cl₂], and, for comparison, the monochelate cis-[Pd(Me₂N(CH₂)₃PPh₂-N,P)Cl₂]. These square-planar complexes exhibit varying degrees of distortion and variable M–N bond lengths dependent not only on the trans influence of P but also on steric effects within the complex. pH-induced chelate ring-opening of cis-[Pt(Me₂N(CH₂)₂PPh₂-P,N)₂]Cl₂ had an associated pK value of 6.9. In contrast, complexes with R¹ and R² = H, n = 2 or 3 or R¹ = H and R² = Me, n = 2, are more difficult to ring-open. Thus the complexes cis-[Pt(Me(H)N(CH₂)₂PPh₂-P,N)₂]Cl₂ and cis-[Pt(H₂N(CH₂)₃PPh₂-P,N)₂]Cl₂, had associated pK values of 2.1 and 2.9, respectively. These aminophosphine complexes may exhibit anticancer activity by two mechanisms: by disrupting mitochondrial membrane potentials as bis-chelated (ring-closed) lipophilic cations, or by direct binding to DNA bases as ring-opened complexes.