Novel DNA-directed alkylating agents consisting of naphthalimide, nitrogen mustard and lexitropsin moieties: synthesis, DNA sequence specificity and biological evaluation.
Novel DNA-directed alkylating agents comprising naphthalimide, nitrogen mustard and lexitropsin moieties have been designed, synthesized and characterized. Their properties have been evaluated with respect to DNA binding ability, sequence preference, influence of flanking sequences on alkylation efficiency and cytotoxic potency against KB human nasopharangeal tumour cells. The results indicate that, in contrast to distamycin and bis-benzimidazole-bearing nitrogen mustard moieties where DNA alkylation is directed to adenine N3 sites in the minor groove, the naphthalimide nitrogen mustards alkylate DNA at accessible guanine N7 sites within the major groove. Structural factors that may affect cytotoxic efficacy are discussed.
Gupta
R
R
Department of Chemistry, University of Alberta, Edmonton, Canada.
Liu
J
J
Xie
G
G
Lown
J W
JW
D015057:1-Naphthylamine / Q000737:chemistry; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D008466:Mechlorethamine / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009429:Netropsin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D007094:Imides; C053654:lexitropsin; D008466:Mechlorethamine; D009429:Netropsin; D004247:DNA; D015057:1-Naphthylamine