Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10592520 | Bioorganic & Medicinal Chemistry Letters | 2012 | 5 Pages |
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 IC50 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.
Keywords
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Physical Sciences and Engineering
Chemistry
Organic Chemistry
Authors
Mallika Alvala, Shubhmita Bhatnagar, Alvala Ravi, Variam Ullas Jeankumar, Thimmappa H Manjashetty, Perumal Yogeeswari, Dharmarajan Sriram,