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

We show that bis(aminophosphine) complexes of the type [M((RRN)-R-1-N-2(CH2)(n)PPh2)(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 R-1 and R-2 (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)(2)PPh2-P,N)(2)]Cl-2, cis-[Pt(H2N(CH2)(3)PPh2-P,N)(2)]Cl-2, and cis-[Pt(Me(H)N(CH2)(2)PPh2-P,N)(2)]Cl-2, the mono-ring-opened complex cis-Pd[(Me2N(CH2)(2)PPh2-N,P)Cl(Me2NH(CH2)(2)PPh2-P](NO3)(2), the di-ring-opened complex cis-[Pt(Me2N(CH2)(3)PPh2-P)(2)Cl-2], and, for comparison, the monochelate cis-[Pd(Me2N(CH2)(3)PPh2-N,P)]Cl-2. 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)(2)PPh2-P,N)(2)]Cl-2 had an associated pK value of 6.9. In contrast, complexes with R-1 and R-2 = H, n = 2 or 3 or R-1 = H and R-2 = Me, n = 2, are more difficult to ring-open. Thus the complexes cis-[Pt(Me(H)N(CH2)(2)PPh2-P,N)(2)]Cl-2 and cis-[Pt(H2N(CH2)(3)PPh2-P,N)(2)]Cl-2, 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.