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Sultams as Dual Inhibitors of Human Carbonic Anhydrase and Thioredoxin Reductase

Aleksandrs Pustenko1, Raitis Bobrovs1, Venkatesan Saravanan2

  • 1Latvian Institute of Organic Synthesis, Riga, Latvia.

Chemmedchem
|July 19, 2026
PubMed

Insights

New sultam-based compounds show promise as dual inhibitors targeting thioredoxin reductase (TrxR1) and tumor-associated carbonic anhydrases (CA IX/XII) to combat cancer drug resistance.

Area of Science:

  • Medicinal Chemistry
  • Oncology
  • Biochemistry

Background:

  • Cancer drug resistance limits single-target therapies.
  • Dual inhibitors offer a strategy to overcome resistance by targeting multiple pathways.

Purpose of the Study:

  • Design, synthesize, and evaluate novel sultam-based N-acyl derivatives.
  • Assess their potential as dual inhibitors of thioredoxin reductase (TrxR1) and tumor-associated carbonic anhydrases (CA IX and XII).

Main Methods:

  • Synthesis of sultam-based N-acyl derivatives (compounds 8a-k and 9a-k).
  • In vitro screening for thioredoxin reductase (TrxR1) inhibition.
  • Carbonic anhydrase (CA) inhibition assays, including selectivity profiling against off-target isoforms (CA I and CA II).

Main Results:

  • Several compounds exhibited activity against TrxR1, with potency dependent on substituent type and orientation.
  • The derivatives displayed significant selectivity for tumor-associated CA IX and XII over non-tumor isoforms CA I and II.
  • No significant inhibition was observed for off-target isoforms CA I and CA II.

Conclusions:

  • Sultam-based N-acyl derivatives show potential as dual-targeting anticancer agents.
  • These compounds effectively inhibit TrxR1 and selectively target CA IX/XII.
  • Further optimization could lead to novel selective, multi-pathway cancer therapies.
Keywords:
biochemistrycancercancer therapycarbonic anhydrasecarbonic anhydrase Ichemistrydrug resistancegene isoformreductasethioredoxin reductase

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