6094-36-6Relevant articles and documents
Discovery of novel chemical scaffolds as RhoA inhibitors using virtual screening, synthesis, and bioactivity evaluation
Zhang, Chao,Wang, Hui-Jie,Bao, Qi-Chao,Bian, Jin-Lei,Yang, Ying-Rui,You, Qi-Dong,Xu, Xiao-Li
, p. 56738 - 56746 (2016/07/06)
RhoA has been implicated in diverse cellular functions and is a potential cancer therapeutic target. Through virtual screening, we have identified a RhoA inhibitor, DDO-5701. DDO-5701 has an affinity to RhoA at the micromolar level in vitro. By structural modifications, considering the binding activity and synthesis ease of DDO-5701, 17 compounds were designed and synthesized accordingly. Among these compounds, 4 compounds (DDO-5713, DDO-5714, DDO-5715, DDO-5716) exhibited higher RhoA inhibition activities than DDO-5701, while DDO-5716 can effectively reverse the functions of breast cancer cells regulated by RhoA. Thus, the rationally designed small molecule inhibitor of RhoA (DDO-5716) is useful for studying the physiological and pathological roles of Rho GTPase. However, DDO-5701 is an approved drug-proglumide, which makes it and its derived compound DDO-5716 more likely to be well tolerated in humans and could quickly lead to further clinical development.
Isotope-labeled differential profiling of metabolites using N-benzoyloxysuccinimide derivatization coupled to liquid chromatography/high-resolution tandem mass spectrometry
Wagner, Michel,Ohlund, Leanne B.,Shiao, Tze Chieh,Vézina, Amélie,Annabi, Borhane,Roy, René,Sleno, Lekha
, p. 1632 - 1640 (2015/11/16)
Rationale An isotopic labeling strategy based on derivatizing amine-containing metabolites has been developed using light (12C6) and heavy (13C6) N-benzoyloxysuccinimide reagents for semi-targeted metabolomic applications. Methods Differentially labeled samples were combined and analyzed simultaneously by liquid chromatography/high-resolution tandem mass spectrometry (LC/HR-MS/MS) to compare relative amounts of amine-containing metabolites. The selectivity of the reaction was determined with model metabolites and was shown to also be applicable to thiol and phenol moieties. The potential for relative quantitation was evaluated in cell extracts and the method was then applied to quantify metabolic perturbations occurring in human cultured cells under normal vs. oxidative stress conditions. Results A total of 279 derivatized features were detected in HL60 cell extracts, 77 of which yielded significant concentration changes upon oxidative stress treatment. Based on accurate mass measurements and MS/MS spectral matching with reference standard solutions, 10 metabolites were clearly identified. Derivatized compounds were found to have diagnostic fragment ions from the reagent itself, as well as structurally informative ions useful for metabolite identification. Conclusions This simple derivatization reaction can be applied to the relative quantitation of amine-, thiol- and phenol-containing compounds, with improved sensitivity and chromatographic peak shapes due to the increased hydrophobicity of polar metabolites not readily amenable to reversed-phase LC/MS analysis.
Discovery of a novel class of 1,3-dioxane-2-carboxylic acid derivatives as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonists
Aoki, Tomiyoshi,Asaki, Tetsuo,Hamamoto, Taisuke,Sugiyama, Yukiteru,Ohmachi, Shinji,Kuwabara, Kenji,Murakami, Kohji,Todo, Makoto
, p. 2128 - 2132 (2008/12/21)
A new series of 1,3-dioxane-2-carboxylic acid derivatives was synthesized and evaluated for agonist activity at human peroxisome proliferator-activated receptor (PPAR) subtypes. Structure-activity relationship studies led to the identification of 2-methyl-c-5-[4-(5-methyl-2-phenyl-1,3-oxazol-4-yl)butyl]-1,3-dioxane-r-2-carboxylic acid 4b as a potent PPARα agonist with high subtype selectivity at human receptor subtypes. This compound exhibited a substantial hypolipidemic effect in type 2 diabetic KK-Ay mice.
