438030-91-2

Upstream product

• 372-09-8 cyanoacetic acid 
• 6315-89-5 3,4-dimethoxyaniline 
• 36140-83-7 1-cyanoacetyl-3,5-dimethylpyrazole 
• 105-56-6 ethyl 2-cyanoacetate 

Relevant academic research and scientific papers

Agonist-mediated switching of ion selectivity in TPC2 differentially promotes lysosomal function

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+- mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.

Structure-based discovery of new selective small-molecule sirtuin 5 inhibitors

Human sirtuin 5 (SIRT5) is a protein deacylase regulating metabolic pathways and stress responses and is implicated in metabolism-related diseases. Small-molecule inhibitors for SIRT5 are sought as chemical tools and potential therapeutics. Herein, we proposed a customized virtual screening approach targeting catalytically important and unique residues Tyr102 and Arg105 of SIRT5. Of the 20 tested virtual screening hits, six compounds displayed marked inhibitory activities against SIRT5. For the hit compound 19, a series of newly synthesized (E)-2-cyano-N-phenyl-3-(5-phenylfuran-2-yl)acrylamide derivatives/analogues were carried out structure–activity relationship analyses, resulting in new more potent inhibitors, among which 37 displayed the most potent inhibition to SIRT5 with an IC50 value of 5.59?±?0.75?μM. The biochemical studies revealed that 37 likely acts via competitive inhibition with the succinyl-lysine substrate, rather than the NAD+ cofactor, and it manifested substantial selectivity for SIRT5 over SIRT2 and SIRT6. This study will aid further efforts to develop new selective SIRT5 inhibitors as tools and therapeutics.

2-Imino 2H-chromene and 2-(phenylimino) 2H-chromene 3-aryl carboxamide derivatives as novel cytotoxic agents: synthesis, biological assay, and molecular docking study

The inhibition of AKR1B10 has been recognized as a potential therapeutic approach to the treatment of various types of cancers. A novel series of compounds with imino-2H-chromen and phenylimino-2H-chromen scaffolds were synthesized by Knoevenagel condensation reaction. The in vitro cytotoxic activity of synthesized compounds was evaluated against MOLT-4 and SK-OV-3 cells. Among the tested compounds, N-(3,4-dimethoxyphenyl)-2-(phenylimino)-2H-chromene-3-carboxamide (8g) demonstrated potent inhibitory activity against both examined cell lines. The results of the molecular docking study suggested that this compound is involved in critical hydrogen-bonding interactions with the Val301 and Lue302 of AKR1B10 catalytic site.

ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2

We have developed a series of novel potent ortho-substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 30 × 10-5 cm/min) is indicative of their potential for intestinal absorption upon oral administration.