| 名稱(chēng) | SRT1720 hydrochloride |
| 描述 | SRT1720 hydrochloride (SRT1720 HCl) is a selective activator of SIRT1 (EC1.5: 0.16 μM) and shows less potent activities on SIRT2/SIRT3 (EC1.5s: 37 μM/300 μM). |
| 細(xì)胞實(shí)驗(yàn) | Cell viability was assessed with a colorimetric assay using MTT as described previously. Apoptosis assay was quantified using Annexin V-FITC/Propidium iodide (PI) apoptosis detection kit, as per manufacturer's instructions, followed by analysis on FACS Calibur [3]. |
| 激酶實(shí)驗(yàn) | In the SIRT1 FP assay, SIRT1 activity was monitored using a 20 amino acid peptide (AcGlu-Glu-Lys(biotin)-Gly-Gln-Ser-Thr-Ser-Ser-His-Ser-Lys(Ac)-Nle-Ser-Thr-Glu-Gly–Lys(MR121 or Tamra)-Glu-Glu-NH2) derived from the sequence of p53. The peptide was N-terminally linked to biotin and C-terminally modified with a fluorescent tag. The reaction for monitoring enzyme activity was a coupled enzyme assay where the first reaction was the deacetylation reaction catalyzed by SIRT1 and the second reaction was cleavage by trypsin at the newly exposed lysine residue. The reaction was stopped and streptavidin was added in order to accentuate the mass differences between substrate and product. In total, 290,000 compounds were screened and 127 hits were confirmed. The sensitivity of the FP assay allowed identification of compounds that exhibited low level activation of SIRT1 (≥17% activation at 20 μM) producing multiple classes of activators representing distinct structural classes. The fluorescence polarization reaction conditions were as follows: 0.5 μM peptide substrate, 150 μM βNAD+, 0-10 nM SIRT1, 25 mM Tris-acetate pH 8, 137 mM Na-Ac, 2.7 mM K-Ac, 1 mM Mg-Ac, 0.05% Tween-20, 0.1% Pluronic F127, 10 mM CaCl2, 5 mM DTT, 0.025% BSA, and 0.15 mM nicotinamide. The reaction was incubated at 37°C and stopped by addition of nicotinamide, and trypsin was added to cleave the deacetylated substrate. This reaction was incubated at 37°C in the presence of 1 μM streptavidin. Fluorescent polarization was determined at excitation (650 nm) and emission (680 nm) wavelengths [1]. |
| 動(dòng)物實(shí)驗(yàn) | Sirtinol (2 mg/kg) was administered by peritoneal injection, whereas SRT1720 (100 mg/kg) was administered through oral gavage 1 hour prior to CS exposure daily for 3 days. In a separate experiment, SRT1720 (25, 50, and 100 mg/kg) or PHA-408 (50 mg/kg) was dissolved in 0.5% carboxymethylcellulose containing 0.025% Tween 20 and injected via oral gavage into the conscious mice 24 hours prior to elastase administration, which was repeated daily (5 days per week) until 21 days after elastase administration. To study the therapeutic effect on emphysema, SRT1720 (100 mg/kg) was orally administered daily for 2 weeks after the development of elastase-induced emphysema [2]. |
| 體外活性 | SRT1720是SIRT1的激活劑（EC1.5 = 0.16 μM，最大激活率 = 781%）。相比于最接近的sirtuin同源體SIRT2和SIRT3，SRT1720對(duì)SIRT1的激活具有選擇性（SIRT2：EC1.5 = 37 μM；SIRT3：EC1.5 > 300 μM）[1]。 |
| 體內(nèi)活性 | SRT1720在小鼠（生物利用度=50%，終末半衰期=約5小時(shí)，曲線(xiàn)下面積（AUC）=7,892 ng h/ml）和大鼠（生物利用度=25%，終末半衰期=約8.4小時(shí)，AUC=3,714 ng/h/ml）中展示了適合體內(nèi)評(píng)估的藥代動(dòng)力學(xué)特性。在DIO小鼠中，采用高脂飲食后，禁食血糖水平升高（范圍120-150 mg dl1）。SRT1720的給藥降低了經(jīng)過(guò)1周治療后的餐后血糖水平，并在3周治療后進(jìn)一步降低，此效果持續(xù)到10周給藥期間。在腹腔內(nèi)糖耐量測(cè)試中，SRT1720組的葡萄糖偏移也顯著減少，與rosiglitazone（一種已被用于治療2型糖尿病的PPARγ激活劑）相當(dāng)[1]。SRT1720減輕了應(yīng)激誘導(dǎo)的早期細(xì)胞衰老并且在小鼠中保護(hù)了免受香煙煙霧和彈性酶引起的肺氣腫的傷害[2]。在動(dòng)物腫瘤模型研究中，SRT1720抑制了MM腫瘤生長(zhǎng)。SRT1720增強(qiáng)了硼替佐米或地塞米松的細(xì)胞毒活性[3]。 |
| 存儲(chǔ)條件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| 溶解度 | H2O : < 1 mg/mL (insoluble or slightly soluble)
DMSO : 55 mg/mL (108.65 mM)
Ethanol : < 1 mg/mL (insoluble or slightly soluble)
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| 關(guān)鍵字 | SRT-1720 Hydrochloride | SRT-1720 hydrochloride | SRT1720 hydrochloride | SRT1720 Hydrochloride |
| 相關(guān)產(chǎn)品 | Fisetin | Salvianolic acid B | Nicotinamide riboside | Nicotinamide | Resveratrol | Dihydrocoumarin | Sirtinol | JGB1741 | SRT 2104 | 3-TYP | SIRT6-IN-5 | MC3482 |
| 相關(guān)庫(kù) | 抗癌活性化合物庫(kù) | 經(jīng)典已知活性庫(kù) | 已知活性化合物庫(kù) | 自噬庫(kù) | 組蛋白修飾化合物庫(kù) | 抗衰老化合物庫(kù) | HIF-1化合物庫(kù) | NO PAINS 化合物庫(kù) | 臨床前化合物庫(kù) | 抗代謝疾病化合物庫(kù) |