SecinH3

Design and Synthesis of New (SecinH3) Derivatives as Potential Cytohesin Inhibitors.[Pubmed:25425752]

Indian J Pharm Sci. 2014 Sep;76(5):387-400.

Cytohesins are small guanine nucleotide exchange factors that stimulate ADP ribosylation factors, Ras-like GTPases, which control various cellular regulatory networks ranging from vesicle trafficking to integrin activation. A small molecule SecinH3 (1,2,4-triazole derivative) in an aptamer displacement assay as a pan-cytohesin Sec7-domain inhibitor was previously identified. Here a series of different SecinH3-analogues was designed and synthesised as potential cytohesin Sec7-domain inhibitors. All final synthesized compounds 6-8, 43-58 and their intermediates were confirmed by (1)H NMR, (13)C NMR and high resolution Mass. Preliminary biological screening of target compounds indictaed that some of the new synthesized SecinH3 derivatives showed higher potency and promising activity more than SecinH3 itself (unpublished results). Compund 9 and 10 were approximate equal to SecinH3 activity as cytohesin antagonist activity. Furthermore compound 52 showed twice inhibition potency if compared to SecinH3.

A trifluoromethylphenyl diazirine-based SecinH3 photoaffinity probe.[Pubmed:22179571]

Chem Commun (Camb). 2012 Jan 30;48(9):1272-4.

The synthesis of a trifluoromethylphenyl diazirine photoaffinity probe of the cytohesin inhibitor SecinH3 is described. The probe exhibits improved labelling efficiency over a benzophenone-based probe and thus is more suitable for photoaffinity labelling in complex biological samples.

Effect of SecinH3 on lung injury induced by sepsis of rats.[Pubmed:26706678]

Asian Pac J Trop Med. 2015 Dec;8(12):1049-1054.

OBJECTIVE: To study effect of SecinH3 on lung injury induced by the sepsis of rats. METHODS: A total of 30 SPF Wistar rats were randomly divided into two groups, including 5 rats in the control group and 25 in the model group. The intraperitoneal injection of endotoxin-lipopolysaccharide (LPS) was performed to build the animal model of sepsis. The blood gas analysis was carried out. Afterwards, change in the expression of pro-inflammatory factors of IL-1, IL-6 and TNF-alpha in the serum were detected. To study the mechanism of SecinH3 in the process of lung injury induced by the sepsis, the rats with the successful modeling of sepsis were randomly divided into two groups. Rats in the SecinH3 group were given the intraperitoneal injection of 100 mug/12 h SecinH3 for 24 h; while rats in the control group were given the injection of same solvent by the same dosage. The blood was drawn from the heart by 500 muL for the blood gas analysis to detect the change in the expression of pro-inflammatory factors of IL-1, IL-6 and TNF-alpha in the treatment group and control group. After separating the lung tissue, the Real-time PCR and western blotting were performed to analyze the effect of SecinH3 on the expression of cytohesins and also discuss the change of epidermal growth factor receptor (EGFR) and p-EGFR related to the signaling pathway of EGFR-p38 mitogen-activated protein kinase that is regulated by cytohesins. RESULTS: Three rats died within 4 h after the injection of LPS, while other 22 ones had the successful modeling, with the success rate of 88%. After being stimulated by LPS, compared with the control group, the arterial partial pressure of oxygen of rats in the treatment group was significantly reduced (P < 0.05), while the partial pressure of CO2 was significantly increased (P < 0.01). After being treated by SecinH3, Pa/O2 was increased with the sepsis, while Pa/CO2 was decreased with the action of SecinH3, which indicated that SecinH3 had the certain 'repairing' ability for the lung injury. SecinH3 might inhibit the cytohesins and then inhibit the phosphorylation of EGFR. CONCLUSIONS: SecinH3 can significantly inhibit the cytohesins and then relieve the lung injury induced by the sepsis of rats.

The cytohesin Steppke is essential for insulin signalling in Drosophila.[Pubmed:17167488]

Nature. 2006 Dec 14;444(7121):945-8.

In metazoans, the insulin signalling pathway has a key function in regulating energy metabolism and organismal growth. Its activation stimulates a highly conserved downstream kinase cascade that includes phosphatidylinositol-3-OH kinase (PI(3)K) and the serine-threonine protein kinase Akt. This study identifies a new component of insulin signalling in Drosophila, the steppke gene (step). step encodes a member of the cytohesin family of guanine nucleotide exchange factors (GEFs), which have been characterized as activators for ADP-ribosylation factor (ARF) GTPases. In step mutant animals both cell size and cell number are reduced, resulting in decreased body size and body weight in larvae, pupae and adults. step acts upstream of PI(3)K and is required for the proper regulation of Akt and the transcription factor FOXO. Temporally controlled interference with the GEF activity of the Step protein by feeding the chemical inhibitor SecinH3 causes a block of insulin signalling and a phenocopy of the step mutant growth defect. Step represses its own expression and the synthesis of growth inhibitors such as the translational repressor 4E-BP. Our findings indicate a crucial role of an ARF-GEF in insulin signalling that has implications for understanding insulin-related disorders, such as diabetes and obesity.

Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance.[Pubmed:17167487]

Nature. 2006 Dec 14;444(7121):941-4.

G proteins are an important class of regulatory switches in all living systems. They are activated by guanine nucleotide exchange factors (GEFs), which facilitate the exchange of GDP for GTP. This activity makes GEFs attractive targets for modulating disease-relevant G-protein-controlled signalling networks. GEF inhibitors are therefore of interest as tools for elucidating the function of these proteins and for therapeutic intervention; however, only one small molecule GEF inhibitor, brefeldin A (BFA), is currently available. Here we used an aptamer displacement screen to identify SecinH3, a small molecule antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization, integrin activation or integrin signalling. The application of SecinH3 in human liver cells showed that insulin-receptor-complex-associated cytohesins are required for insulin signalling. SecinH3-treated mice show increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, cytohesin inhibition results in hepatic insulin resistance. Because insulin resistance is among the earliest pathological changes in type 2 diabetes, our results show the potential of chemical biology for dissecting the molecular pathogenesis of this disease.

SecinH3 is an antagonist of cytohesins with IC50s of 5.4 μM, 2.4 μM, 5.4 μM, 5.6 μM, 5.6 μM and 65 μM for hCyh1, hCyh2, mCyh3, hCyh3, drosophila steppke and yGea2-S7, respectively.

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