Intercalator-linked cisplatin: synthesis and antitumor activity of cis-dichloroplatinum(II) complexes connected to acridine and phenylquinolines by one methylene chain

Three novel intercalator-linked cisplatin-type platinum complexes, cis-[PtCl2(9-(2-aminoethyl)aminomethylacridine)] (1), cis-[PtCl2(4-(2-aminoethyl) aminomethyl-2-phenylquinoline)] (2), and cis-[PtCl2(8-(2-aminoethyl)aminomethyl-2-phenylquinoline)] (3) were synthesized, The structure of 1 was determined by X-ray crystallography (triclinic, space group P (1) over bar with a=15.007(6), b=15.597(4), c = 10.398(3) Angstrom, alpha=98.51(3)degrees, beta=96.79(3)degrees, gamma = 114.61(2)degrees, Z=4, R = 0.053, R-w=0.063). The antitumor activity of the platinum complexes was investigated against the HeLa cell. Compound 3 was the most cytotoxic among the complexes synthesized here and was more effective than cisplatin. It was suggested from microscopic analysis that the acridine complex 1, which had no cytotoxicity against the HeLa cell, was not incorporated in the nucleus of the cell. Against the P388 cell, however, complex 1 gave a more therapeutic result than 3. The covalent binding ability of the cisplatin moiety was suppressed significantly in these compounds. The results of molecular mechanics showed that intercalation and covalent binding could be compatible. The cytotoxicity and DNA binding ability of phenylquinoline-type ligands were also studied to evaluate the intrinsic cytotoxicity of the intercalator. From the duplex DNA denaturation experiment and fluorescent ethidium displacement assay, the DNA binding affinities of the ligands are in agreement with the cytotoxicity of these compounds and the corresponding platinum complexes. (C) 1998 Elsevier Science S.A. All rights reserved.