Mono- and dysfunctional nitrogen mustard analogues of the DNA minor groove binder pibenzimol. Synthesis, cytotoxicity and interaction with DNA.
Two series of mono- and dysfunctional aniline mustards linked to a bisbenzimidazole minor groove binder have been prepared using a new method (polyphosphate ester-mediated direct coupling of appropriate mustard acids with a preformed advanced phenylenediamine intermediate). As the linker chain attaching the mustard was lengthened the binding site size of the compounds to calf thymus DNA remained essentially constant at 2.6 nucleotides, but reversible binding strength declined by a factor of 2. Analogues with longer linker chains alkylated DNA much more rapidly than those with shorter chains, consistent with the electronic factors. The short chain analogues also failed to alkylate a 120 bp HindIII to Bg/II fragment of the gpt gene, as measured by gel electrophoresis cleavage assays. The longer chain analogues (both mono- and dysfunctional mustards) showed patterns of DNA alkylation that varied with chain length. In particular, while most compounds showed substantial N7 alkylation at many guanine residues, the analogue with a (CH2)3 linker chain showed strong alkylation at adenine sites in poly-AT regions. For the longer chain analogues, the bifunctional mustards were substantially (10- to 20-fold) more cytotoxic than the corresponding monofunctional analogues.
Smaill
J B
JB
Cancer Research Laboratory, School of Medicine, University of Auckland, New Zealand.
Fan
J Y
JY
Papa
P V
PV
O'Connor
C J
CJ
Denny
W A
WA
D000478:Alkylation; D000818:Animals; D001483:Base Sequence; D006690:Bisbenzimidazole / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D004247:DNA / Q000187:drug effects*; D004591:Electrophoresis, Polyacrylamide Gel; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008466:Mechlorethamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D008466:Mechlorethamine; D004247:DNA; D006690:Bisbenzimidazole