Isolation and structural analysis of the covalent adduct formed between a bis-amino mitoxantrone analogue and DNA: a pathway to major-minor groove cross-linked adducts

Authors

Shyam K. Konda, University of New South Wales
Celine Kelso, University of WollongongFollow
Jelena Medan, The Walter & Eliza Hall Institute of Medical Research, La Trobe University
Brad E. Sleebs, The Walter & Eliza Hall Institute of Medical Research, University of Melbourne
Don R. Phillips, La Trobe University
Suzanne M. Cutts, La Trobe University
J Grant Collins, University of New South WalesFollow

RIS ID

113809

Publication Details

Konda, S. K., Kelso, C., Medan, J., Sleebs, B. E., Phillips, D. R., Cutts, S. M. & Collins, J. Grant. (2016). Isolation and structural analysis of the covalent adduct formed between a bis-amino mitoxantrone analogue and DNA: a pathway to major-minor groove cross-linked adducts. Organic and Biomolecular Chemistry, 14 (43), 10217-10221.

Abstract

The major covalent adduct formed between a ¹³C-labelled formaldehyde activated bis-amino mitoxantrone analogue (WEHI-150) and the hexanucleotide d(CG^5MeCGCG)₂ has been isolated by HPLC chromatography and the structure determined by NMR spectroscopy. The results indicate that WEHI-150 forms one covalent bond through a primary amine to the N-2 of the G₂ residue, with the polycyclic ring structure intercalated at the ^5MeC₃pG₄/G₁₀p^5MeC₉ site. Furthermore, the WEHI-150 aromatic ring system is oriented approximately parallel to the long axis of the base pairs, with one aliphatic side-chain in the major groove and the other side-chain in the minor groove. This study indicates that mitoxantrone derivatives like WEHI-150 should be capable of forming major-minor groove cross-linked adducts that will likely produce considerably different intracellular biological properties compared to known anthracycline and anthracenedione anticancer drugs.