2-(Methyl(phenyl)amino)-<i>N</i>-(phenyloxyphenyl)acetamide structural motif representing a framework for selective SIRT2 inhibition

Kaya S. G., Eren G., Massarotti A., Bakar-Ates F., Ozkan E., Gozelle M., ...Daha Fazla

DRUG DEVELOPMENT RESEARCH, cilt.85, sa.4, 2024 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 85 Sayı: 4
  • Basım Tarihi: 2024
  • Doi Numarası: 10.1002/ddr.22224
  • Dergi Adı: DRUG DEVELOPMENT RESEARCH
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, Biotechnology Research Abstracts, CAB Abstracts, Chemical Abstracts Core, EMBASE, International Pharmaceutical Abstracts, Veterinary Science Database
  • Anahtar Kelimeler: MCF-7, optimization, selectivity, sirtuin, α-tubulin
  • Gazi Üniversitesi Adresli: Evet

Özet

The mammalian cytoplasmic protein SIRT2, a class III histone deacetylase family member, possesses NAD(+)-dependent lysine deacetylase/deacylase activity. Dysregulation of SIRT2 has been implicated in the pathogenesis of several diseases, including neurological and metabolic disorders and cancer; thus, SIRT2 emerges as a potential therapeutic target. Herein, we identified a series of diaryl acetamides (ST61-ST90) by the structural optimization of our hit STH2, followed by enhanced SIRT2 inhibitory potency and selectivity. Among them, ST72, ST85, and ST88 selectively inhibited SIRT2 with IC50 values of 9.97, 5.74, and 8.92 mu M, respectively. Finally, the entire study was accompanied by in silico prediction of binding modes of docked compounds and the stability of SIRT2-ligand complexes. We hope our findings will provide substantial information for designing selective inhibitors of SIRT2.