Substituted 9-aminoacridine-4-carboxamides tethered to platinum(II)diamine complexes: chemistry, cytotoxicity and DNA sequence selectivity.
Three platinum complexes in which substituted (7-OMe, 9-NH(2); 7-F, 9-NH(2); and 7-H, 9-NH(CH(2))(2)OH) 9-aminoacridine-4-carboxamides were tethered to a platinum(II)diamine moiety were synthesised and characterised at the chemical and biological level. These variants showed a decrease in cytotoxicity, as measured by IC(50) values in HeLa cells, when compared with the parent 7-H, 9-NH(2) compound. The 7-F and 9-NH(CH(2))(2)OH substituents gave rise to a small decrease in cytotoxicity, and the 7-OMe substituent resulted in a larger decrease in cytotoxicity. Their binding to purified pUC19 plasmid DNA was investigated and it was found that the addition of 7-F, 9-NH(CH(2))(2)OH and especially the 7-OMe substituents, resulted in reduced DNA binding. This correlated well with the IC(50) cytotoxicity values. However, the DNA sequence selectivity was unaffected by the addition of these moieties.
Carland
Michael
M
School of Chemistry, The University of Melbourne, Grattan Street, Parkville, Victoria 3052, Australia.
Grannas
Martin J
MJ
Cairns
Murray J
MJ
Roknic
Vanessa J
VJ
Denny
William A
WA
McFadyen
W David
WD
Murray
Vincent
V
D000609:Aminoacridines / Q000138:chemical synthesis / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry; D003603:Cytotoxins / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry*
D000609:Aminoacridines; D000970:Antineoplastic Agents; D003603:Cytotoxins; D009944:Organoplatinum Compounds; C054505:9-aminoacridine-4-carboxamide; D004247:DNA