Synthesis, characterization, and biological activity of cis-diammineplatinum(II) complexes of the DNA intercalators 9-aminoacridine and chloroquine

Article abstract of DOI:10.1021/ja00160a044

The anticancer drug cis-diamminedichloroplatinum(II) reacts with the DNA intercalators 9-aminoacridine (9-AA) and chloroquine (CQ) to form the novel complexes cis-[Pt(NH₃)₂(N9-9-AA)Cl](NO₃) (1), cis-[Pt(NH₃)₂(N9-9-AA)₂](NO₃) ₂ (2), and cis-[Pt(NH₃)₂(N1-HCQ)Cl](NO₃)₂ (3). Interestingly, platinum coordinates to the deprotonated exocyclic amino group of 9-aminoacridine in 1 and 2, with the proton being transferred to the endocyclic nitrogen atom N10, as revealed by X-ray crystal structure determinations. As a consequence, the acridine rings are asymmetrically positioned with respect to the platinum coordination plane, resulting in short (2.390 ? in 1-MeOH and 2.458 A1? in 2-MeOH) nonbonded contacts between platinum and one of the acridine ring protons (H1). NMR spectroscopic studies demonstrated the persistence of this structure in DMF solutions of the complexes, the short Pt-H1 distances resulting in paramagnetic deshielding of the H1 protons by approximately 3.32 (1) and 2.25 (2) ppm. The Pt-H1 interactions are not agostic, however, since no reduction in the magnitude of ¹J_C1-^H1 coupling is observed. In contrast to 9-aminoacridine, chloroquine preferentially coordinates to platinum via the less hindered endocyclic N1 ring nitrogen atom. Since both diastereoisomers of 3 are observed by ¹H NMR spectroscopy, rotation about the Pt-N1 bond is slow on the NMR time scale. Complexes of the general formula Cis-[Pt(NH₃)₂(INT)Cl]ⁿ⁺, where INT is a DNA intercalator such as 9-AA or CQ, have the potential to bind both covalently and intercalatively to DNA and, consequently, are potential antitumor agents. Complexes 1 and 3 were determined to be extremely toxic in animal screens, however, precluding their use as drugs.