Oral Presentation Royal Australian Chemical Institute National Congress 2026

Investigating the therapeutic potential of synthesised TA/TMIO hybrids for age-related macular degeneration  (136891)

Neil Delos Reyes 1 , Carl Soltau 2 , Davinia Beaver 1 , Steven Bottle 2 , Tim Dargaville 2 , Nigel Barnett 1
  1. Clem Jones Centre for Regenerative Medicine, Bond University, Robina, QUEENSLAND, Australia
  2. School of Chemistry and Physics, Queensland University of Technology, Brisbane City, Queensland, Australia

Age-related macular degeneration (AMD) is a complex, multifactorial retinal disease driven by aging, photooxidative stress, and para‑inflammation. Dry AMD, which accounts for over 80% of global cases, currently has no effective treatment1. Its progression is marked by the accumulation of inflammatory and oxidative byproducts (i.e. drusen)2. Existing FDA-approved therapeutics for dry AMD target the complement cascade; however, these agents do not restore vision and may increase the risk of wet AMD which leads to vision loss3. An alternative anti-inflammatory approach is modulation of the glucocorticoid receptor (GR) pathway4. Triamcinolone acetonide (TA), a GR agonist, is clinically used as the anti-inflammatory component of triple therapy for wet AMD, which has reduced retreatment frequency in patients5. 

Prolonged corticosteroid use, however, can induce oxidative stress6. Recent advances in nitroxide chemistry have enabled the conjugation of corticosteroids such as TA to superoxide dismutase mimetics like 1,1,3,3‑tetramethylisoindolinyl‑oxyl (TMIO) via ester or ether linkages, potentially uniting antioxidant and anti-inflammatory activity in a single hybrid molecule7. This study aimed to synthesise novel TA/TMIO hybrids and evaluate their therapeutic potential under inflammatory stress in retinal cells. 

The synthesis produced hybrids in good yield. GR binding assays showed therapeutically relevant but higher IC50 values for the hybrids compared with TA, consistent with in silico docking predictions. In 661W mouse photoreceptor cells, neither the hybrids, parent compounds, nor co‑treatments affected resazurin reduction, indicating unchanged metabolic capacity. However, pre-treatment with the biologically cleavable, ester‑linked hybrid 1‑NR‑2 (2 µM) significantly mitigated cytokine‑induced inflammation to levels comparable to TA. In contrast, neither 5‑carboxy‑TMIO nor the non‑cleavable, ether‑linked hybrid 1‑NR‑25 (2 µM) affected MCP‑1 release. 

In conclusion, ester‑linked hybridisation of TMIO to TA increases GR IC50 but preserves TA’s anti-inflammatory activity, supporting a promising strategy for multifunctional therapeutics targeting dry AMD. Future work includes evaluating the hybrids’ antioxidant properties. 

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