SYNTHESIS, CHARACTERIZATION, AND BIOLOGICAL-ACTIVITY OF CIS-DIAMMINEPLATINUM(II) COMPLEXES OF THE DNA INTERCALATORS 9-AMINOACRIDINE AND CHLOROQUINE

The anticancer drug a>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)C1](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 Å in 1-MeOH and 2.458 Å in 2-MeOH) nonbonded contacts between platinum and one of the acridine ring protons (HI). NMR spectroscopic studies demonstrated the persistence of this structure inDMF solutions of the complexes, the short Pt-Hl distances resulting in paramagnetic deshielding of the HI protons by approximately 3.32 (1) and 2.25 (2) ppm. The Pt-Hl interactions are not agostic, however, since no reduction in the magnitude of 1JC1-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-Nl 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. © 1990, American Chemical Society. All rights reserved.