title: Design and synthesis of a DNA-crosslinking azinomycin analogue.
abstract: The azinomycins are potent antitumour antibiotics that are able to crosslink DNA, but are relatively unstable and unlikely to progress as therapeutic candidates. A prototype analogue 4 with more clinical potential has been designed and synthesised and incorporates the epoxide function of the azinomycins and a nitrogen mustard. Two further analogues 5 and 6 that can alkylate DNA but cannot crosslink the duplex have also been synthesised. Compound 4 crosslinks DNA efficiently at nM concentrations. Compounds 4-6 were submitted to the NCI 60 cell line screen and have similar antitumour activity, although 4 is slightly less active than the non-crosslinking compounds. These observations will be important in the design of further azinomycin analogues with antitumour activity.
authors.affiliation: Dept. of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK WC1N 1AX.
authors.forename: Maxwell A
authors.initials: MA
authors.lastname: Casely-Hayford
authors.forename: Klaus
authors.initials: K
authors.lastname: Pors
authors.forename: Colin H
authors.initials: CH
authors.lastname: James
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Patterson
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Mark
authors.initials: M
authors.lastname: Searcey
mesh_terms: D000478:Alkylation; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis*; D053961:Azabicyclo Compounds; D003432:Cross-Linking Reagents / Q000138:chemical synthesis*; D004247:DNA / Q000737:chemistry*; D004151:Dipeptides; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000737:chemistry; D006020:Glycopeptides / Q000138:chemical synthesis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008466:Mechlorethamine / Q000494:pharmacology; D008956:Models, Chemical; D009281:Naphthalenes / Q000138:chemical synthesis; D010455:Peptides / Q000138:chemical synthesis*; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D053961:Azabicyclo Compounds; D003432:Cross-Linking Reagents; D004151:Dipeptides; D004852:Epoxy Compounds; D006020:Glycopeptides; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; C051055:azinomycin B; C051054:azinomycin A; D008466:Mechlorethamine; D004247:DNA