title: Functionalized tetrahydro-1H-pyrido[4,3-b]indoles: a novel chemotype with Sirtuin 2 inhibitory activity.
abstract: Sirtuins are protein deacylases with regulatory roles in metabolism and stress response. Functionalized tetrahydro-1H-pyrido[4,3-b]indoles were identified as preferential sirtuin 2 inhibitors, with in vitro inhibitory potencies in the low micromolar concentrations (IC50 3-4 μM) for the more promising candidates. The functional relevance of sirtuin inhibition was corroborated in western blots that showed hyperacetylation of p53 and α-tubulin in treated HepG2 and MDA-MB-231 cells. Molecular docking showed that the tetrahydropyridoindole scaffold was positioned in the NAD + pocket and the acetylated substrate channel of the sirtuin 2 protein by van der Waals/hydrophobic, H bonding and stacking interactions. Functionalized tetrahydropyridoindoles represent a novel class of sirtuin 2 inhibitors that could be further explored for its therapeutic potential.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore.
authors.forename: Tianming
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: Key Laboratory of Applied Marine Biotechnology, Ministry of Education, School of Marine Sciences, Ningbo University, Fenghua Road 818, Jiangbei District, Ningbo, Zhejiang 315211, People's Republic of China.
authors.forename: Hai-xiao
authors.initials: HX
authors.lastname: Jin
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Drive, 117597, Republic of Singapore.
authors.forename: Gautam
authors.initials: G
authors.lastname: Sethi
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore. Electronic address: phagoml@nus.edu.sg.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056565:Sirtuin 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D011725:Pyridines; C000596932:tetrahydro-1H-pyrido(3,4-b)indole; C474199:SIRT2 protein, human; D056565:Sirtuin 2
keywords: Apoptosis; Growth inhibition; Hyperacetylation of p53 and α-tubulin; Molecular docking; Sirtuin 2 inhibition; Tetrahydropyridoindoles