Platinum(II) complexes of dipyridophenazine as metallointercalators for DNA and potent cytotoxic agents against carcinoma cell lines

The synthesis and spectroscopic characterization of a new class of DNA-intercalating platinum(II) complexes, [Pt(dppz) (tN^∧C)] CF₃SO₃ (dppz = dipyrido[3,2-a:2′,3′-c]phenazine, tN^∧CH = 4-tert-butyl-2-phenylpyridine) and [Pt(dppz)(L)₂](CF₃SO₃)₂ (L = 1-methylimidazole (Meim-1) or 4-aminopyridine (NH₂py-4)) are described. All the complexes are photoluminescent in degassed acetonitrile at room temperature. [Pt(dppz)(tN^∧C)]CF₃SO₃ shows a vibronic structured emission (λ_max = 477 nm) which is assigned to the intraligand transition (IL) of the C-deprotonated 4-tert-butyl-2-phenylpyridine ligand. Both [Pt(dppz)(Meim-1)₂]-(CF₃SO₃)₂ and [Pt(dppz)(NH₂py-4)₂]-(CF₃SO₃) ₂ display a lower energy emission band with λ_max at 558 nm, which is originated from a ³MLCT state [5d(Pt) →π* (dppz)]. The binding reactions of platinum(II) complexes with double-stranded DNA (dsDNA) were studied by spectroscopic methods and the intrinsic binding constants (K) are 1.1 × 10⁴ - 1.3 × 10⁴ dm³mol^-1. The results of gel electrophoresis and UV melting experiments revealed that they interact strongly with DNA. In aerated aqueous Tris buffer solution, [Pt(dppz)(tN^∧C)]CF₃SO₃ is nonemissive. Upon intercalation of [Pt(dppz)-(tN^∧C)]CF₃SO₃ into calf thymus DNA (ctDNA), a low energy emission with λ_max = 650 nm is developed and this is ascribed to exciplex formation between the excited state of [Pt(dppz)(tN^∧C)]⁺ with the DNA base pairs. The cytotoxicity of [Pt(dppz)(tN^∧C)]CF₃SO₃ was compared to that of cisplatin using human carcinoma KB-3-1 and its multidrug-resistant subclone KB-V1 cell lines, which is 10 and 40 times more potent than cisplatin in the killing of KB-3-1 and KB-V1 cells, respectively.

© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999