title: DNA-binding properties and antitumour activity of monofunctional alkylating groups attached to the DNA-intercalating chromophore phenanthridine: n-bromoalkylphenanthridinium bromides.
abstract: We have synthesised an homologous series of n-bromoalkylphenanthridinium bromides and studied their DNA-binding and antitumour properties. Each of these compounds has the capacity both to intercalate and alkylate DNA. Dialysis measurements reveal a relatively high affinity for calf thymus DNA, being about 10(5) M-1 at ionic strength 0.01. Incubating calf thymus DNA-ligand complexes having a ligand-to-basepair ratio of 0.4 at 37 degrees C for 18 h leads to maximum alkylation levels of about one ligand molecule bound irreversibly per 40 basepairs. The reactivity of these compounds towards DNA is chain-length dependent, the n-decyl compound, for example, requiring about 10-times the ligand-to-basepair input ratio of the n-hexyl derivative to reach the same level of alkylation. The limited degree of alkylation is a consequence of conversion of the alkylbromides to the less reactive alkylchlorides in the buffer medium. The results of DNA sequencing experiments indicate that the n-hexyl derivative alkylates at guanines occurring in 5'-GT-3' sequences and in runs of guanines [(Gp)n]. The corresponding n-decyl compound, on the other hand, is highly selective for guanines in 5'-GT-3' sequences only and also reacts weakly with some adenines. None of the phenanthridinium compounds showed significant antitumour activity in the P388 murine leukaemia test system.
authors.affiliation: Peter MacCallum Cancer Institute, Melbourne, Parkville, Australia.
authors.forename: G
authors.initials: G
authors.lastname: Wickham
authors.forename: A S
authors.initials: AS
authors.lastname: Prakash
authors.forename: L P
authors.initials: LP
authors.lastname: Wakelin
authors.forename: W D
authors.initials: WD
authors.lastname: McFadyen
mesh_terms: D000477:Alkylating Agents / Q000138:chemical synthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D001483:Base Sequence; D002021:Buffers; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004278:DNA, Superhelical / Q000378:metabolism; D003956:Dialysis; D004354:Drug Screening Assays, Antitumor; D007364:Intercalating Agents / Q000138:chemical synthesis; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010617:Phenanthridines / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010957:Plasmids; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000477:Alkylating Agents; D000970:Antineoplastic Agents; D002021:Buffers; D004278:DNA, Superhelical; D007364:Intercalating Agents; D010617:Phenanthridines; D004247:DNA