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

Abstract

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 (λmax = 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 λmax 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 λmax = 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.