A scaffold replacement approach towards new sirtuin 2 inhibitors

• Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD(+)-dependent protein deacylases regulating the acylation state of epsilon-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.

Ämnesord

NATURVETENSKAP  -- Kemi (hsv//swe)

NATURAL SCIENCES  -- Chemical Sciences (hsv//eng)

Nyckelord

Scaffold

Sirtuin

SIRT2

Inhibitor

Benzothiazine-1

1-dioxide

Benzothiadiazine-1

1-dioxides

Saccharin

Quinolin-4-one

Docking

force-field

chroman-4-one

protein

brain

Biochemistry & Molecular Biology

Pharmacology & Pharmacy

Chemistry

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)