title: Synthesis of novel DNA cross-linking antitumour agents based on polyazamacrocycles.
abstract: We are seeking to develop more effective alkylating agents as antitumour agents. In previous work conformationally restricted nitrogen mustards were synthesised containing piperidine or pyrrolidine rings. The free bases were designed to be bifunctional alkylating agents via aziridinium ion formation and the effects of varying the distances between the two alkylating sites were studied. Some efficient cross-linkers of naked DNA were prepared but few of these compounds exhibited significant cytotoxicity in human tumour cells in vitro. We have extended this work by making tri- and tetra-azamacrocyclic compounds containing two to four potential alkylating sites. Most of these compounds were powerful DNA alkylating agents and showed cytotoxicity (IC(50) values 6-100microM) comparable with chlorambucil (45microM) and melphalan (8.5microM). In particular the cyclen derivative 2a was more than 10(4) times more effective at cross-linking DNA (2a XL(50)<<10nM) than chlorambucil (XL(50) 100microM), and showed significant cytotoxicity in human tumour cells in vitro.
authors.affiliation: Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Parker
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Anderson
authors.forename: C Caroline
authors.initials: CC
authors.lastname: O'Hare
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Lacy
authors.forename: John P
authors.initials: JP
authors.lastname: Bingham
authors.forename: David J
authors.initials: DJ
authors.lastname: Robins
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel / Q000379:methods; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure
chemical_list: D000970:Antineoplastic Agents; D001372:Aza Compounds; D003432:Cross-Linking Reagents; D047028:Macrocyclic Compounds; D004247:DNA