cis-Dichloroplatinum(II) complexes tethered to 9-aminoacridine-4-carboxamides: synthesis and action in resistant cell lines in vitro.
A series of intercalator-tethered platinum(II) complexes PtLCl(2) have been prepared where L are the diamine ligands N-[2-[(aminoethyl)amino]ethyl]-9-aminoacridine-4-carboxamide, N-[3-[(2-aminoethyl)amino]propyl]-9-aminoacridine-4-carboxamide, N-[4-[(2-aminoethyl)amino]butyl]-9-aminoacridine-4-carboxamide and N-[5-[(aminoethyl)amino]pentyl]-9-aminoacridine-4-carboxamide and N-[6-[(aminoethyl)amino]hexyl]-9-aminoacridine-4-carboxamide. The activity of the complexes was assessed in the CH-1, CH-1cisR, 41M, 41McisR and SKOV-3 cell lines. The compounds with the shorter linker chain lengths are generally the most active against these cell lines and are much more toxic than Pt(en)C1(2). For example, for the n=2 compound the IC(50) values are 0.017 microM (CH-1), 1.7 microM (41M), 1.4 microM (SKOV-3) and the resistance ratios are 51 (CH-1cisR) and 1.6 (41McisR). For the untethered analogue Pt(en)C1(2) the IC(50) values are 2.5 microM (CH-1), 2.9 microM (41M), 45 microM (SKOV-3) and the resistance ratios are 2.8 (CH-1cisR) and 4.1 (41McisR). The very large differential in IC(50) values 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 compounds.
Holmes
R J
RJ
School of Chemistry, The University of Melbourne, Grattan Street, Parkville, Victoria, Australia, 3052.
McKeage
M J
MJ
Murray
V
V
Denny
W A
WA
McFadyen
W D
WD
D000609:Aminoacridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004351:Drug Resistance; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000609:Aminoacridines; D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C054505:9-aminoacridine-4-carboxamide; C002892:platinum ethylenediamine dichloride