117423-75-3Relevant articles and documents
Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT
Yagci, Semih,Gozelle, Mahmut,Kaya, Selen Gozde,Ozkan, Yesim,Aksel, Ahmet Bugra,Bakar-Ates, Filiz,Dundar, Yasemin,Eren, Gokcen
, (2021/01/07)
Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.
N,N-Dimethyl Glycine-Promoted Ullmann Coupling Reaction of Phenols and Aryl Halides
Ma, Dawei,Cai, Qian
, p. 3799 - 3802 (2007/10/03)
(Matrix presented) Ullmann-type diaryl ether synthesis can be performed at 90°C using either aryl iodides or aryl bromides as the substrates under the assistance of N,N-dimethylglycine.
Benzophenone Dicarboxylic Acid Antagonists of Leukotriene B4. 1. Structure-Activity Relationships of the Benzophenone Nucleus
Gapinski, D. Mark,Mallett, Barbara E.,Froelich, Larry L.,Jackson, William T.
, p. 2798 - 2807 (2007/10/02)
A series of lipophilic benzophenone dicarboxylic acid derivatives was prepared which inhibited the binding of the potent chemotaxin leukotriene B4 to its receptor(s) on intact human neutrophils.With a radioligand-binding assay as a measure of receptor affinity, a structure-activity relationship for this series was investigated.Both acidic residues were required for receptor-binding activity.The relative orientation of the two acidic groups was important for optimal binding.Replacement of the carbonyl group of the benzophenone with a variety of polar and nonpolar linking groups lead to only small changes in binding affinity, indicating the linking group may not be involved in receptor recognition.Further structure-activity relationships within this series are reported in an accompanying paper.