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
Bioorganic & Medicinal Chemistry | PERGAMON-ELSEVIER SCIENCE LTD | Published : 2020
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 mode..View full abstract
This work was supported by grants from the NHMRC, ARC and the CASS Foundation (SMC and DRP), an AusAID ADS Scholarship and also support from the La Trobe University Postgraduate Write-up Award (PWA). BES is a Corin Centenary Fellow. BJE is an employee of Nyrada Inc and declares no conflict of interest.