Formaldehyde-activated WEHI-150 induces DNA interstrand crosslinks with unique structural features

Paul P Pumuye; Benny J Evison; Shyam K Konda; J Grant Collins; Celine Kelso; Jelena Medan; Brad E Sleebs; Keith Watson; Don R Phillips; Suzanne M Cutts

doi:10.1016/j.bmc.2019.115260

Formaldehyde-activated WEHI-150 induces DNA interstrand crosslinks with unique structural features

Bioorg Med Chem. 2020 Feb 1;28(3):115260. doi: 10.1016/j.bmc.2019.115260. Epub 2019 Dec 14.

Authors

Affiliations

¹ La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia.
² School of Science, University of New South Wales, Canberra 2610, Australia.
³ School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia.
⁴ La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia; Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia.
⁵ Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
⁶ Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia.
⁷ La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia. Electronic address: s.cutts@latrobe.edu.au.

PMID: 31870833
DOI: 10.1016/j.bmc.2019.115260

Abstract

Mitoxantrone is an anticancer anthracenedione that can be activated by formaldehyde to generate covalent drug-DNA adducts. Despite their covalent nature, these DNA lesions are relatively labile. It was recently established that analogues of mitoxantrone featuring extended side-chains terminating in primary amino groups typically yielded high levels of stable DNA adducts following their activation by formaldehyde. In this study we describe the DNA sequence-specific binding properties of the mitoxantrone analogue WEHI-150 which is the first anthracenedione to form apparent DNA crosslinks mediated by formaldehyde. The utility of this compound lies in the versatility of the covalent binding modes displayed. Unlike other anthracenediones described to date, WEHI-150 can mediate covalent adducts that are independent of interactions with the N-2 of guanine and is capable of adduct formation at novel DNA sequences. Moreover, these covalent adducts incorporate more than one formaldehyde-mediated bond with DNA, thus facilitating the formation of highly lethal DNA crosslinks. The versatility of binding observed is anticipated to allow the next generation of anthracenediones to interact with a broader spectrum of nucleic acid species than previously demonstrated by the parent compounds, thus allowing for more diverse biological activities.

Keywords: Anthracenediones; Cancer chemotherapy; DNA sequence specificity; Drug-DNA adducts; Mitoxantrone analogues.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cattle
DNA / drug effects*
Dose-Response Relationship, Drug
Formaldehyde / chemistry
Formaldehyde / pharmacology*
Mass Spectrometry
Mitoxantrone / analogs & derivatives
Mitoxantrone / chemistry
Mitoxantrone / pharmacology*
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Formaldehyde
DNA
calf thymus DNA
Mitoxantrone