Frontiers in bioscience (Landmark edition) · 2026
Immunomodulatory Effect of Aza-Spirocyclic Frameworks.
СтатьяНазвание и аннотация: Перевод в очереди
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Prajapati Anjali, Tatikonda Rajitha Rajeshwar, Chada Raji Reddy, Bonam Srinivasa Reddy
Аннотация
BACKGROUND: Immunomodulators play a central role in the treatment of cancer and immune-mediated disorders. Small-molecule immunomodulators are particularly attractive due to their structural diversity, pharmacological versatility, and potential for oral administration. This study aimed to investigate the immunomodulatory potential of newly synthesized aza-spirocyclic derivatives.
METHODS: A series of novel aza-spirocyclic compounds was evaluated for cytotoxicity in RAW264.7 murine macrophages. Immunomodulatory activity was assessed by quantifying nitric oxide (NO) production and profiling pro- and anti-inflammatory cytokines in macrophages and murine splenocytes. In vitro anti-inflammatory effects were further examined using a lipopolysaccharide (LPS)-induced inflammation model. Mechanistic insights were explored using molecular docking and immuno-informatics analyses.
RESULTS: All compounds were non-toxic at the tested concentrations. Most derivatives failed to induce NO production, indicating an absence of danger-associated molecular pattern (DAMP)-like activity. Several compounds significantly reduced the pro-inflammatory cytokine interleukin-6 (IL-6) while increasing the anti-inflammatory cytokine IL-10 in vitro. In the LPS-induced inflammation model, four compounds notably suppressed IL-6 and enhanced IL-10 expression. The binding affinities obtained from docking, along with in vitro validation of these compounds on Janus kinases (JAKs) signaling, suggested that compounds AS8 and AS10 modulated inflammatory signaling pathways.
CONCLUSION: The synthesized aza-spirocyclic derivatives exhibit promising anti-inflammatory profiles, characterized by IL-6 suppression and IL-10 enhancement. These findings position aza-spirocyclic scaffolds as candidates for the development of next-generation small-molecule immunomodulators.
METHODS: A series of novel aza-spirocyclic compounds was evaluated for cytotoxicity in RAW264.7 murine macrophages. Immunomodulatory activity was assessed by quantifying nitric oxide (NO) production and profiling pro- and anti-inflammatory cytokines in macrophages and murine splenocytes. In vitro anti-inflammatory effects were further examined using a lipopolysaccharide (LPS)-induced inflammation model. Mechanistic insights were explored using molecular docking and immuno-informatics analyses.
RESULTS: All compounds were non-toxic at the tested concentrations. Most derivatives failed to induce NO production, indicating an absence of danger-associated molecular pattern (DAMP)-like activity. Several compounds significantly reduced the pro-inflammatory cytokine interleukin-6 (IL-6) while increasing the anti-inflammatory cytokine IL-10 in vitro. In the LPS-induced inflammation model, four compounds notably suppressed IL-6 and enhanced IL-10 expression. The binding affinities obtained from docking, along with in vitro validation of these compounds on Janus kinases (JAKs) signaling, suggested that compounds AS8 and AS10 modulated inflammatory signaling pathways.
CONCLUSION: The synthesized aza-spirocyclic derivatives exhibit promising anti-inflammatory profiles, characterized by IL-6 suppression and IL-10 enhancement. These findings position aza-spirocyclic scaffolds as candidates for the development of next-generation small-molecule immunomodulators.