Design and synthesis of a DNA-crosslinking azinomycin analogue.
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.
Casely-Hayford
Maxwell A
MA
Dept. of Pharmaceutical and Biological Chemistry, School of Pharmacy, University of London, 29-39 Brunswick Square, London, UK WC1N 1AX.
Pors
Klaus
K
James
Colin H
CH
Patterson
Laurence H
LH
Hartley
John A
JA
Searcey
Mark
M
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
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