Design and synthesis of a DNA-crosslinking azinomycin analogue

• Published in: Organic & biomolecular chemistry Vol. 3; no. 19; pp. 3585 - 3589
• Main Authors: Casely-Hayford, MA, Pors, K, James, CH, Patterson, LH, Hartley, JA, Searcey, M
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 07.10.2005
• Subjects: Alkylation; Antibiotics, Antineoplastic - chemical synthesis; Azabicyclo Compounds; Chemistry; Chemistry, Organic; Cross-Linking Reagents - chemical synthesis; Dipeptides; DNA - chemistry; Drug Screening Assays, Antitumor; Epoxy Compounds - chemistry; Glycopeptides - chemical synthesis; Humans; Mechlorethamine - pharmacology; Models, Chemical; Naphthalenes - chemical synthesis; Peptides - chemical synthesis; Physical Sciences; Science & Technology; Tumor Cells, Cultured; AGENT; ANTITUMOR ANTIBIOTICS; NAPHTHOATE; CARZINOPHILIN; MECHANISM; ALKYLATION; CLEAVAGE; CYTOTOXICITY; SEQUENCE SELECTIVITY
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/b508908e

The azinomycins are potent antitumour 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.