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A scaffold replacement approach towards new sirtuin 2 inhibitors
Tina Seifert1, Marcus Malo1, Tarja Kokkola2
1Department of Chemistry and Molecular Biology, Medicinal Chemistry, University of Gothenburg, SE-412 96 Göteborg, Sweden.
Bioorganic & Medicinal Chemistry
|December 19, 2019
Summary
Researchers developed new SIRT2 inhibitors using benzothiadiazine-1,1-dioxide scaffolds to improve drug properties. These compounds show high SIRT2 inhibitory activity, offering potential for treating diseases linked to sirtuin dysfunction.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Pharmacology
Background:
- Sirtuins (SIRTs) are NAD+-dependent deacetylases crucial for cellular processes.
- Dysregulated SIRT activity is linked to diseases like cancer, diabetes, and neurodegeneration.
- Previous research identified chroman-4-one/chromone derivatives as SIRT2 inhibitors.
Purpose of the Study:
- To design and synthesize novel SIRT2 inhibitors with improved physicochemical properties.
- To explore bioisosteric replacements for the lipophilic chroman-4-one/chromone core.
- To identify new scaffolds with high SIRT2 inhibitory potential.
Main Methods:
- Synthesis of new derivatives based on quinolin-4(1H)-one, bicyclic secondary sulfonamides, saccharins, and benzothiadiazine-1,1-dioxide scaffolds.
- Evaluation of synthesized compounds for SIRT inhibitory activity, focusing on SIRT2.
- Molecular modeling to understand the binding interactions of novel inhibitors.
Main Results:
- Benzothiadiazine-1,1-dioxide derivatives exhibited the most potent SIRT2 inhibition among the tested scaffolds.
- The new scaffolds offer a less lipophilic alternative to previous chroman-4-one/chromone inhibitors.
- Molecular modeling provided insights into the binding modes of the novel SIRT2 inhibitors.
Conclusions:
- Benzothiadiazine-1,1-dioxide derivatives represent a promising new class of SIRT2 inhibitors.
- Scaffold hopping strategies can overcome limitations of existing SIRT inhibitor chemotypes.
- These findings may facilitate the development of new therapeutics for SIRT-related diseases.
