Synthesis and anti-tumour activity of the spatially-separated mustard bis-N,N'-[3-(N-(2-chloroethyl)-N-ethyl)amino-5-[N,N-dimethylamino)methy l)-aminophenyl]-1,4-benzenedicarboxamide, which alkylates DNA exclusively at adenines in the minor groove.
The mustard derivative, bis-N,N'-[3-(N-(2-chloroethyl)-N-ethyl)amino-5- [N,N-dimethylamino)methyl)aminophenyl]-1,4-benzenedicarboxamide has been synthesized from 3-acetamido-5-nitrobenzoic acid in a 6-step procedure. This compound alkylates exclusively in the minor groove of DNA, at the N3 site of adenines occurring in sequences of runs of adenines and (to a small extent) at 5'-TA and 5'-AT sites. Gel electrophoresis studies and in vitro cytotoxicity assays against repair-deficient AA8 mutant cell lines show it has a high degree of DNA interstrand cross-linking ability.
Prakash
A S
AS
Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.
Valu
K K
KK
Wakelin
L P
LP
Woodgate
P D
PD
Denny
W A
WA
D000477:Alkylating Agents / Q000138:chemical synthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001483:Base Sequence; D002460:Cell Line; D004249:DNA Damage; D004269:DNA, Bacterial / Q000737:chemistry; D015195:Drug Design; D066298:In Vitro Techniques; D051379:Mice; D008969:Molecular Sequence Data; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D004269:DNA, Bacterial; D009588:Nitrogen Mustard Compounds