title: 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.
abstract: The major covalent adduct formed between a13C-labelled formaldehyde activated bis-amino mitoxantrone analogue (WEHI-150) and the hexanucleotide d(CG5MeCGCG)2has 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 G2residue, with the polycyclic ring structure intercalated at the5MeC3pG4/G10p5MeC9site. 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.affiliation: School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, ACT, 2600 Australia. g.collins@adfa.edu.au.
authors.forename: Shyam K
authors.initials: SK
authors.lastname: Konda
authors.affiliation: School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
authors.forename: Celine
authors.initials: C
authors.lastname: Kelso
authors.affiliation: Chemical Biology Division The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052 Australia and Department of Biochemistry and Genetics La Trobe University, VIC 3083, Australia. s.cutts@latrobe.edu.au.
authors.forename: Jelena
authors.initials: J
authors.lastname: Medan
authors.affiliation: Chemical Biology Division The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052 Australia and Department of Medical Biology The University of Melbourne, VIC 3010, Australia.
authors.forename: Brad E
authors.identifier: http://orcid.org/0000-0001-9117-1048
authors.initials: BE
authors.lastname: Sleebs
authors.affiliation: Department of Biochemistry and Genetics La Trobe University, VIC 3083, Australia. s.cutts@latrobe.edu.au.
authors.forename: Don R
authors.initials: DR
authors.lastname: Phillips
authors.affiliation: Department of Biochemistry and Genetics La Trobe University, VIC 3083, Australia. s.cutts@latrobe.edu.au.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Cutts
authors.affiliation: School of Physical, Environmental and Mathematical Sciences, University of New South Wales, Australian Defence Force Academy, ACT, 2600 Australia. g.collins@adfa.edu.au.
authors.forename: J Grant
authors.initials: JG
authors.lastname: Collins
mesh_terms: D004247:DNA / Q000737:chemistry*; D008942:Mitoxantrone / Q000737:chemistry*; D008958:Models, Molecular; D009690:Nucleic Acid Conformation; D009841:Oligonucleotides / Q000737:chemistry
chemical_list: D009841:Oligonucleotides; D004247:DNA; D008942:Mitoxantrone