cis-dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-arboxamides: synthesis and action in resistant cell lines in vitro

A series of intercalator-tethered platinum(II) complexes PtLCl2 have been p repared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-am inoacridine N-[3-[(2-aminoethyl)amino]propyl]-9-aminoacridine-4-carboxamide , N-[4-[(2-aminoethyl)amino]butyl]-9-aminoacridine-34-carboxamide and N-[5- [(aminoethyl)amino]pentyl]-9-aminoacridine-4-carboxmide and N-[6-[(aminoeth yl)amino]hexyl]-9-aminoacridine-4-carboxamide. The activity of the complexe s was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. T he compounds with the shorter linker chain lengths are generally the most a ctive against these cell lines and are much more toxic than Pt(en)Cl-2. For example, Tor the n=2 compound the IC50 values are 0.017 muM (CH-1), 1.7 mu M (41M), 1.4 muM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1 .6 (41McisR). For the untethered analogue Pt(en)Cl-2 the IC50 values are 2. 5 muM (CH-1), 2.9 muM (41M), 45 muM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC,, value s between the CH-1 and CH-1cisR pair of cell lines for the 9-aminoacridine- 4-carboxamide tethered platinum complexes indicates that repair of platinum -induced DNA damage may be a major determinant of the activity of these com pounds. (C) 2001 Elsevier Science B.V. All rights reserved.