Synthesis and evaluation of DNA-targeted spatially separated bis(aniline mustards) as potential alkylating agents with enhanced DNA cross-linking capability.
DNA-targeted separated bis-mustards were synthesized by attaching aniline mono-mustards at the 4- and 9-positions of the DNA-intercalating ligand 9-aminoacridine-4-carboxamide, with the intention of improving the low cross-link to monoadduct ratio found with most alkylating agents. The geometry of these compounds requires that, when the acridine binds to DNA by intercalation, one alkylating moiety is delivered to each DNA groove. Gel electrophoretic studies show that only one arm of these compounds (probably that attached to the 9-position) alkylates DNA, such alkylation occurring specifically in the major groove at the N7 of guanines. Cell-line studies confirm that the mode of cytotoxicity of these compounds (unlike that of untargeted aniline bis-mustards of comparable reactivity) is due to bulky DNA monoadduct formation. It is concluded that more information is required about the exact orientation of the initial monoadducts before ligands with specific DNA cross-linking ability can be designed.
Gourdie
T A
TA
Cancer Research Laboratory, School of Medicine, University of Auckland, New Zealand.
Prakash
A S
AS
Wakelin
L P
LP
Woodgate
P D
PD
Denny
W A
WA
D000477:Alkylating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000478:Alkylation; D000816:Aniline Mustard / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D015394:Molecular Structure; D010957:Plasmids / Q000187:drug effects; D013329:Structure-Activity Relationship
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D007202:Indicators and Reagents; D004247:DNA; D000816:Aniline Mustard