3709-16-8Relevant articles and documents
Discovery of 5-Benzylidene-2-phenyl-1,3-dioxane-4,6-diones as Highly Potent and Selective SIRT1 Inhibitors
Li, Chunpu,Hu, Sha-Sha,Yang, Lisheng,Wang, Min,Long, Jian-Dong,Wang, Bing,Han, Haozhen,Zhu, Haoran,Zhao, Sen,Liu, Jing-Gen,Liu, Dongxiang,Liu, Hong
, p. 397 - 403 (2021)
SIRT1, a member of the sirtuin family, catalyzes the deacetylation of proteins with the transformation of NAD+ into nicotinamide and 2′-O-acetyl-ADP-ribose. Selective SIRT1/2 inhibitors have potential application in the chemotherapy of colorectal carcinoma, prostate cancer, and myelogenous leukemia. Here we identified novel SIRT1 inhibitors with the scaffold of 5-benzylidene-2-phenyl-1,3-dioxane-4,6-dione. The most potent inhibitor 12n displayed an IC50 of 460 nM and a selectivity for SIRT1 over SIRT2, SIRT3, and SIRT5 of 113.5-, 254.3-, and 10.83-fold, respectively. It did not affect the activity of SIRT6. To elucidate the inhibitory mechanism, we determined the inhibition type of the inhibitor by enzyme kinetic analysis, showing that the inhibitor was competitive to the acetyl peptide and noncompetitive to NAD+. Further, the interaction of the inhibitor in SIRT1 was studied by using molecular docking, which was validated by the structure-activity relationship analysis of the inhibitors and the site-directed mutagenesis of SIRT1. Consistent with the in vitro assays, the inhibitors increased the acetylation level of p53 in a concentration-dependent manner in cells.
1,3-dioxane-4,6-dione compound, preparation method, medicine composition and application thereof
-
Paragraph 0081; 0083; 0084; 0085, (2018/11/03)
The invention discloses a 1,3-dioxane-4,6-dione compound, a preparation method, a medicine composition and application thereof. The structure of the compound is as shown in a formula I, and the definition of each substituent is as shown in the description
A new class of inhibitors of secretory phospholipase A2: enolized 1,3-dioxane-4,6-dione-5-carboxamides
Breitenstein, W.,Maerki, F.,Roggo, S.,Wiesenberg, I,Pfeilschifter, J.,et al.
, p. 649 - 658 (2007/10/02)
Enolized 1,3-dioxane-4,6-dione-5-carboxamides a were identified as a new class of inhibitors of secretory phospholipase A2 from human polymorphonuclear leucocytes (h-PMN PLA2).Among the more than 30 compounds synthesized, the most potent inhibitors (IC50 0.6-10 μM) were found in the series of 2,4-disubstituted phenyl analogues of a.Compound 1a was selected for evaluation of its biological profile.This substance potently inhibited secretory PLA2s from several sources other than human PMNs, with a clear preference for group II over group I PLA2, whereas humancytosolic PLA2 and phospholipase C were not significantly affected.Inhibition of h-PMN PLA2 was calcium-dependent.In intact mammalian cells stimulated in vitro, the release of arachidonic acid and the generation of prostaglandins and leukotrienes were inhibited at concentrations compatible with inhibition of PLA2 as an underlying mechanism.In animal models in vivo (carragheenan oedema, adjuvant arthritis, pertussis pleurisy) 1a showed antiinflammatory activity, although the effect was rather weak compared with standard reference compounds. secretory human PMN phospholipase A2 / enolized 1,3-dioxane-4,6-dione-5-carboxamide inhibitors / cellular eicosanoid synthesis / in vivo antiinflammatory activity / molecular modelling / structure-activity relationship
