title: Novel acridinedione derivatives: design, synthesis, SIRT1 enzyme and tumor cell growth inhibition studies.
abstract: A new scaffold N-(9-(ortho/meta/para-(benzyloxy)phenyl)-3,3,6,6-tetramethyl-1,8-dioxo-1,2,3,4,5,6,7,8-octahydroacridin-10(9H)-yl) isonicotinamide (H1-3) was discovered as a hSIRT1 inhibitor through virtual screening of in-house database. Based on these hits, a library of compounds were designed, synthesized and tested for in vitro hSIRT1 activity. The most potent compound 4d in the series showed a significant inhibition of SIRT1 activity. Further antitumor studies of compound 4d, showed a dose dependent increase in acetylation of p53K382 and decrease in SIRT1 with an IC(50) of 0.25 μM in MDA-MB231 breast cancer cell lines. Individual 3D-QSAR analysis using Schrödinger showed distribution of hydrophobic and non polar positive co-efficient at ortho position essential for bioactivity based on 4d.
authors.affiliation: Drug Discovery Research Laboratory, Department of Pharmacy, Birla Institute of Technology and Science, Pilani-Hyderabad Campus, Hyderabad 500 078, India.
authors.forename: Mallika
authors.initials: M
authors.lastname: Alvala
authors.forename: Shubhmita
authors.initials: S
authors.lastname: Bhatnagar
authors.forename: Alvala
authors.initials: A
authors.lastname: Ravi
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.forename: Thimmappa H
authors.initials: TH
authors.lastname: Manjashetty
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000107:Acetylation; D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006131:Growth Inhibitors / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D021281:Quantitative Structure-Activity Relationship; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D006131:Growth Inhibitors; C447939:SIRT1 protein, human; D056564:Sirtuin 1