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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

Journal Article


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Abstract


  • The major covalent adduct formed between a 13C-labelled formaldehyde activated bis-amino mitoxantrone analogue (WEHI-150) and the hexanucleotide d(CG5MeCGCG)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/G10p5MeC9 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.

Authors


  •   Konda, Shyam K. (external author)
  •   Kelso, Celine
  •   Medan, Jelena (external author)
  •   Sleebs, Brad E. (external author)
  •   Phillips, Don R. (external author)
  •   Cutts, Suzanne M. (external author)
  •   Collins, J Grant. (external author)

Publication Date


  • 2016

Citation


  • 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.

Scopus Eid


  • 2-s2.0-84994559816

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=5622&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/4597

Number Of Pages


  • 4

Start Page


  • 10217

End Page


  • 10221

Volume


  • 14

Issue


  • 43

Abstract


  • The major covalent adduct formed between a 13C-labelled formaldehyde activated bis-amino mitoxantrone analogue (WEHI-150) and the hexanucleotide d(CG5MeCGCG)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/G10p5MeC9 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.

Authors


  •   Konda, Shyam K. (external author)
  •   Kelso, Celine
  •   Medan, Jelena (external author)
  •   Sleebs, Brad E. (external author)
  •   Phillips, Don R. (external author)
  •   Cutts, Suzanne M. (external author)
  •   Collins, J Grant. (external author)

Publication Date


  • 2016

Citation


  • 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.

Scopus Eid


  • 2-s2.0-84994559816

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=5622&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/4597

Number Of Pages


  • 4

Start Page


  • 10217

End Page


  • 10221

Volume


  • 14

Issue


  • 43