二苯并氮卓作用機(jī)制 - Medchemexpress - MCE中國

1、Product Data SheetYO-01027Cat. No.: HY-13526CAS No.: 209984-56-5分式: CHFNO分量: 463.48作靶點(diǎn): Notch; -secretase作通路: Neuronal Signaling; Stem Cell/Wnt儲(chǔ)存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 33 mg/mL (71.20 mM)H2O : 0.1 mg/mL (insoluble)* means soluble, but sat

2、uration unknown.SolventMass1 mg 5 mg 10 mgConcentration制備儲(chǔ)備液1 mM 2.1576 mL 10.7880 mL 21.5759 mL5 mM 0.4315 mL 2.1576 mL 4.3152 mL10 mM 0.2158 mL 1.0788 mL 2.1576 mL請(qǐng)根據(jù)產(chǎn)品在不同溶劑中的溶解度選擇合適的溶劑配制儲(chǔ)備液；旦配成溶液，請(qǐng)分裝保存，避免反復(fù)凍融造成的產(chǎn)品失效。儲(chǔ)備液的保存式和期限：-80C, 6 months; -20C, 1 month。-80C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?6 個(gè)內(nèi)使，-20C 儲(chǔ)存時(shí)，請(qǐng)?jiān)?1 個(gè)內(nèi)使。體內(nèi)實(shí)驗(yàn)

3、請(qǐng)根據(jù)您的實(shí)驗(yàn)動(dòng)物和給藥式選擇適當(dāng)?shù)娜芙獍?。以下溶解案都?qǐng)先按照 In Vitro 式配制澄清的儲(chǔ)備液，再依次添加助溶劑：為保證實(shí)驗(yàn)結(jié)果的可靠性，澄 的儲(chǔ)備液可以根據(jù)儲(chǔ)存條件，適當(dāng)保存；體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使； 以下溶劑前顯的百分 指該溶劑在您配制終溶液中的體積占；如在配制過程中出現(xiàn)沉淀、析出現(xiàn)象，可以通過加熱和/或超聲的式助溶1. 請(qǐng)依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 2.5 mg/mL (5.39 mM); Suspended solution; Need ultrasonic此案可獲

4、得 2.5 mg/mL (5.39 mM) 的均勻懸濁液，懸濁液可于服和腹腔注射。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 400 L PEG300 中，混合均勻；向上述體系中加50 L Tween-80，混合均勻；然后繼續(xù)加 450 L 理鹽定容 1 mL。2. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 2.5 mg/mL (5.39 mM); Suspended solution; Need ultrasonicPage 1 of 2 www.MedChemE此案可獲得

5、 2.5 mg/mL (5.39 mM) 的均勻懸濁液，懸濁液可于服和腹腔注射。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 900 L 20% 的 SBE-CD 理鹽溶液中，混合均勻。3. 請(qǐng)依序添加每種溶劑： 10% DMSO 90% corn oilSolubility: 2.5 mg/mL (5.39 mM); Clear solution此案可獲得 2.5 mg/mL (5.39 mM，飽和度未知) 的澄 溶液，此案不適于實(shí)驗(yàn)周 期在半個(gè)以上的實(shí)驗(yàn)。以 1 mL 作液為例，取 100 L 25.0 mg/mL 的澄 DMSO 儲(chǔ)備液加到 9

6、00 L 油中，混合均勻。BIOLOGICAL ACTIVITY物活性 YO-01027 (Dibenzazepine; DBZ)效的 -分泌酶抑制劑，裂解 Notch 和 APPL 的 IC50 分別為 2.92 和 2.64 nM。IC & Target IC50: 2.920.22 (Notch), 2.640.30 (APPL) nM1體外研究 Increasing concentrations of DBZ administered to APPL- or Notch-expressing cells leads to the progressiveaccumulation of A

7、PPL CTF fragments and a decrease in NICD production in a strictly dose-dependent manner1. Themolecular targets of CE and DBZ are the N-terminal fragment of presenilin 1 within the -secretase complex2.體內(nèi)研究 DBZ blocks activated Notch1 signaling in abdominal aortic aneurysm (AAA) tissue from both Ang I

8、I-infused Apo E-/-mice and human undergoing AAA repair. DBZ markedly prevents Ang II-stimulated accumulation of macrophages and CD4+ T cells, and ERK-mediated angiogenesis, simultaneously reverses Th2 response, in vivo3. Administration ofDBZ markedly attenuates renal fibrosis and expression of fibro

9、tic markers, including collagen 11/31, fibronectin,and -smoothmuscle actin. DBZ significantly inhibits ureteral obstruction -induced expression of transforming growthfactor (TGF)- , phosphorylated Smad 2, and Smad 34.PROTOCOLCell Assay 1 DBZ (0.1, 1, 2.5, 5, 7.5, 10, 25, 50, 100, 250 nM) are added t

10、o the S2 cell medium upon induction of Notch or APPLexpression, 6 h before protein harvesting. For each sample, the same inhibitor is also included at the correspondingconcentration in the lysis buffer for protein extraction and immunoblot analysis1.MCE has not independently confirmed the accuracy o

11、f these methods. They are for reference only.Animal Mice: Male wild-type (WT) C57BL/6J and Apo E-/- mice are used in the study. Ang II-treated mice are received anAdministration 3 intraperitoneal injection of either saline vehicle or -secretase inhibitor, dibenzazepine (DBZ) (1 mg/kg/d, dissolved in

12、saline) 1 day before mini-pump implantation, and the treatment continued daily for 4 weeks. The blood pressure ismeasured in conscious mice using a computerized tail-cuff system. All mice are anesthetized. The aortic tissues areremoved and prepared for further histological and molecular analysis3.MC

13、E has not independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Groth C, et al. Pharmacological analysis of Drosophila melanogaster gamma-secretase with respect to differential proteolysis of Notch and APP. MolPharmacol. 2010 Apr;77(4):567-74.2. Fuwa H, et a

14、l. Divergent synthesis of multifunctional molecular probes to elucidate the enzyme specificity of dipeptidic gamma-secretase inhibitors. ACSChem Biol. 2007 Jun 15;2(6):408-18.Page 2 of 3 www.MedChemE3. Zheng YH, et al. Notch -secretase inhibitor dibenzazepine attenuates angiotensin II-induced abdominal aortic aneurysm in ApoE knockout mice bymultiple mechanisms. PLoS One. 2013 Dec 16;8(12):e83310.4. Xiao Z, et al. The Notch -secretase inhibitor ameliorates kidney fibrosis via inhibition of TGF-/Smad2/3 signaling pathway activation. Int J Biochem CellBiol. 2014 Oct;55:65-7