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.