title: Synthesis of new bifunctional compounds which selectively alkylate guanines in DNA.
abstract: The aim of this work was to develop new bifunctional alkylating agents which damage DNA in a selective manner. In order to extend our previously published work on conformationally restricted nitrogen mustards containing one piperidine ring, new bispiperidine derivatives were designed with varying lengths of carbon chain between the two rings and structure-activity relationships in these systems were studied. Thus samples of new bispiperidine salts 22-26 with chloromethyl groups at the 2-positions and a bridge between the two nitrogen atoms of 2-6 carbon atoms were synthesized. The analogous new bis(p-nitrophenylcarbamates) 17-21 were also prepared. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation with different distances between the two alkylating sites. The bispiperidines 22-24 were shown to alkylate guanines at the 7-position in the major groove of DNA more selectively than melphalan. The bispiperidine 22 with the shortest two carbon bridge was the most reactive but it was less cytotoxic than melphalan in a human colon carcinoma cell line (IC50 value approximately 30 microM) and in a human chronic myeloid leukaemia cell line (IC50 value approximately 12 microM). The most cytotoxic compound in the latter cell line was the carbamate 17, with an IC50 value of approximately 0.3 microM, and carbamates 17, 19 and 20 were most potent in a panel of human ovarian carcinoma cell lines. These compounds also showed circumvention of acquired cisplatin resistance in three paired cell lines. The carbamates 17-21, however, were less efficient at alkylating and cross-linking naked DNA than the bispiperidines 22-26.
authors.affiliation: Department of Chemistry, University of Glasgow, UK.
authors.forename: N D
authors.initials: ND
authors.lastname: Henderson
authors.forename: S M
authors.initials: SM
authors.lastname: Lacy
authors.forename: C C
authors.initials: CC
authors.lastname: O'Hare
authors.forename: J A
authors.initials: JA
authors.lastname: Hartley
authors.forename: S
authors.initials: S
authors.lastname: McClean
authors.forename: L P
authors.initials: LP
authors.lastname: Wakelin
authors.forename: L R
authors.initials: LR
authors.lastname: Kelland
authors.forename: D J
authors.initials: DJ
authors.lastname: Robins
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000494:pharmacology; D001483:Base Sequence; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D006147:Guanine / Q000378:metabolism*; D019073:HT29 Cells; D006801:Humans; D008969:Molecular Sequence Data
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003432:Cross-Linking Reagents; D006147:Guanine; D004247:DNA