Oral Presentation Royal Australian Chemical Institute National Congress 2026

Molecular Hybridisation of Corticosteroids and Nitroxides: A Therapeutic Platform for Multifunctional Agents with Tunable Redox Bioactivity (136869)

Carl Soltau 1 2 , Debottam Sinha 3 , Alexander Martyn 4 , Jerry Tay 1 , Mark Adams 1 , Steven Bottle 2
  1. Cancer and Ageing Research Program, Centre for Genomics and Personalised Health, Brisbane, QLD, Australia
  2. School of Chemistry and Physics, Queensland University of Technology, Brisbane, QLD, Australia
  3. Frazer Institute (University of Queensland), Translational Research Institute, Woolloongabba, QLD, Australia
  4. Centre for Advanced Imaging, University of Queensland, St Lucia, QLD, Australia

Multifactorial diseases such as cancer are driven by interconnected inflammatory signalling and redox imbalance, motivating the development of multifunctional small-molecule therapeutics capable of modulating multiple pathways simultaneously. We report the design, synthesis, and biological evaluation of steroidal–nitroxide hybrid compounds that combine glucocorticoid receptor (GR) targeting with redox-active functionality. Hybridisation at the corticosteroid C21 position using short linkers produced compounds retaining GR activity and suppressing inflammatory cytokine signalling, while displaying linker-dependent intracellular stability and redox behaviour. Cleavable hybrids generated transient oxidative perturbations, whereas metabolically stable analogues induced sustained reactive oxygen species (ROS) elevation, establishing clear structure–activity relationships between linker chemistry, metabolism, and biological outcome.

Initial biological evaluation in cervical cancer models demonstrated that nitroxide-functionalised steroid hybrids exhibit potent antiproliferative activity and synergistically enhance cisplatin efficacy while maintaining normal cell viability. Mechanistic investigation linked these effects to ROS-mediated pathways, including elevated intracellular oxidative stress and depletion of glutathione levels when used in combination therapy. Building on these insights, a lead hybrid compound displayed concentration-dependent antiproliferative activity across lung, breast, and prostate cancer cell models and potentiated cisplatin efficacy, achieving comparable growth inhibition at reduced drug doses. Sustained ROS induction suggests disruption of tumour redox adaptation as a key mechanism underlying the observed chemo-sensitisation. Collectively, these results demonstrate the broader translational potential of steroidal–nitroxide hybrids as redox-modulating therapeutic scaffolds beyond a single cancer type.

Together, this integrated body of work establishes steroidal–nitroxide hybrids as a tunable platform for multifunctional drug design against redox-related disease.

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