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SRT2104 (GSK2245840) Sale

(Synonyms: 玻玛西林) 目录号 : GC15109

SRT2104 (GSK2245840) is a highly selective small-molecule activator of Sirtuin 1 (SIRT1).

SRT2104 (GSK2245840) Chemical Structure

Cas No.:1093403-33-8

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Sample solution is provided at 25 µL, 10mM.

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实验参考方法

Cell experiment [1]:

Cell lines

KGN, a human ovarian granulosa-like tumor cell line, derived from a granulosa cell tumors (GCT) patient

Preparation Method

The cells were seeded on cell culture dishes (5 × 105) and treated with EX 527 (50 µM) or SRT2104 (10 µM) for 24 h. Then, the cells were harvested and used for the SIRT Activity Assay Kit.

Reaction Conditions

10 µM, for 24 h

Applications

SRT2104 (GSK2245840) significantly increased SIRT1 deacetylation activity.

Animal experiment [2]:

Animal models

Male C57BL/6J mice

Preparation Method

For the longevity study, diets were started at 28 weeks of age after randomization into two groups of 100 mice per group. Mice were fed a standard AIN-93G diet (SD; carbohydrate:protein:fat ratio of 64:19:17 percent of kcal), or a SD supplemented with SRT2104. SRT2104 was added at a dose of 1.33 g drug per kg of chow, formulated to provide daily doses of ~ 100 mg drug kg-1 bodyweight.

Dosage form

100 mg kg-1

Applications

SRT2104 supplementation resulted in improved survival of SD-fed mice with an increase in mean lifespan of 9.7% and in maximum lifespan (defined as the 10th percentile) of 4.9%.

References:

[1]: Schmid N, Dietrich KG, Forne I, Burges A, Szymanska M, Meidan R, Mayr D, Mayerhofer A. Sirtuin 1 and Sirtuin 3 in granulosa cell tumors. International Journal of Molecular Sciences. 2021 Feb 19;22(4):2047.
[2]: Mercken EM, Mitchell SJ, Martin©\Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye©\Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG. SRT 2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging cell. 2014 Oct;13(5):787-96.

产品描述

SRT2104 (GSK2245840) is a highly selective small-molecule activator of Sirtuin 1 (SIRT1), penetrated the blood-brain barrier, attenuated brain atrophy, improved motor function, and protected against diabetes-induced aortic endothelial dysfunction [1,2].

Treatment with SRT2104 (3µM, 48h) decreased P53 and Ac-P53 protein levels, but not P53 mRNA in HG-treated endothelial cells (ECs) [2]. Treatment with SRT2104 also (3µM, 48h) increased SIRT1 in protein level [2]. SRT2104 (10 µM, 24 h) significantly increased cell counts of KGN (an established cellular model for the majority of granulosa cell tumors (GCTs) and were used to explore the role of SIRT1), and SRT2104 significantly increased SIRT1 deacetylation activity [3].

SRT2104 (fed 0.5% with diet) improved motor function, increased survival, and attenuated brain atrophy in N171-82Q Huntington's disease (HD) mice [1]. SRT2104 (100 mg kg-1) treatment improves whole-body physiology and extends lifespan in mice fed a standard diet [4]. SRT2104-treated mice significantly reduced fasting blood glucose and insulin levels, and insulin resistance index [4]. SRT2104 (100 mg kg-1) treatment increases mitochondrial content and suppresses the inflammatory response [4]. SRT2104 alleviated muscle loss in hindlimb-unloading model in mice, and involutional and disuse-mediated osteoporosis [4]. SRT2104 improved diabetic nephropathy. SRT2104 (100 mg kg-1) protected diabetes mellitus (DM)-induced albuminuria and renal pathological injuries, and the was protective effect abrogated by P53 [5].

References:
[1]. Jiang M, Zheng J, Peng Q, Hou Z, Zhang J, Mori S, Ellis JL, Vlasuk GP, Fries H, Suri V, Duan W. Sirtuin 1 activator SRT 2104 protects Huntington's disease mice. Annals of clinical and translational neurology. 2014 Dec;1(12):1047-52.
[2]. Wu H, Wu J, Zhou S, Huang W, Li Y, Zhang H, Wang J, Jia Y. SRT2104 attenuates diabetes-induced aortic endothelial dysfunction via inhibition of P53. Journal of Endocrinology. 2018 Apr 1;237(1):1-4.
[3]. Schmid N, Dietrich KG, Forne I, Burges A, Szymanska M, Meidan R, Mayr D, Mayerhofer A. Sirtuin 1 and Sirtuin 3 in granulosa cell tumors. International Journal of Molecular Sciences. 2021 Feb 19;22(4):2047.
[4]. Mercken EM, Mitchell SJ, Martin?\Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye?\Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG. SRT 2104 extends survival of male mice on a standard diet and preserves bone and muscle mass. Aging cell. 2014 Oct;13(5):787-96.
[5]. Ma F, Wu J, Jiang Z, Huang W, Jia Y, Sun W, Wu H. P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2019 Aug 1;1866(8):1272-81.

SRT2104 (GSK2245840) 是 Sirtuin 1 (SIRT1) 的高选择性小分子激活剂,可穿透血脑屏障,减轻脑萎缩,改善运动功能,并防止糖尿病引起的主动脉内皮功能障碍 [1,2 ].

用 SRT2104(3µM,48 小时)处理可降低 HG 处理的内皮细胞 (EC) 中的 P53 和 Ac-P53 蛋白水平,但不会降低 P53 mRNA [2]。 SRT2104 治疗 (3µM, 48h) 也增加了 SIRT1 的蛋白质水平[2]。 SRT2104 (10 µM, 24 h) 显着增加 KGN 的细胞计数(大多数颗粒细胞瘤 (GCT) 的已建立细胞模型,用于探索 SIRT1 的作用),SRT2104 显着增加 SIRT1 去乙酰化活性[3]。

SRT2104(0.5% 的饮食喂养)改善了 N171-82Q 亨廷顿病 (HD) 小鼠 [1] 的运动功能,增加了存活率,并减轻了脑萎缩。 SRT2104 (100 mg kg-1) 治疗改善了喂食标准饮食的小鼠的全身生理并延长了寿命[4]。 SRT2104 处理的小鼠显着降低了空腹血糖和胰岛素水平,以及胰岛素抵抗指数[4]。 SRT2104 (100 mg kg-1) 处理可增加线粒体含量并抑制炎症反应[4]。 SRT2104 减轻了小鼠后肢卸载模型中的肌肉损失,以及退化和废用介导的骨质疏松症[4]。 SRT2104 改善了糖尿病肾病。 SRT2104 (100 mg kg-1) 保护糖尿病 (DM) 引起的白蛋白尿和肾脏病理损伤,且保护作用被 P53[5] 消除。

Chemical Properties

Cas No. 1093403-33-8 SDF
别名 玻玛西林
化学名 4-methyl-N-[2-[3-(morpholin-4-ylmethyl)imidazo[2,1-b][1,3]thiazol-6-yl]phenyl]-2-pyridin-3-yl-1,3-thiazole-5-carboxamide
Canonical SMILES CC1=C(SC(=N1)C2=CN=CC=C2)C(=O)NC3=CC=CC=C3C4=CN5C(=CSC5=N4)CN6CCOCC6
分子式 C26H24N6O2S2 分子量 516.64
溶解度 ≥ 6.46 mg/mL in DMSO with gentle warming 储存条件 Store at -20°C
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1 mM 1.9356 mL 9.6779 mL 19.3558 mL
5 mM 0.3871 mL 1.9356 mL 3.8712 mL
10 mM 0.1936 mL 0.9678 mL 1.9356 mL
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Research Update

P53/NRF2 mediates SIRT1's protective effect on diabetic nephropathy

Diabetic nephropathy (DN) is the leading cause of end stage renal disease, posing a severe threat to public health. Previous studies reported the protective role of sirtuin 1 (SIRT1) in DN, encouraging the investigation of more potent and specific SIRT1 activators. SRT2104 is a novel, first-in-class, highly selective small-molecule activator of SIRT1, with its effect and mechanism unknown on DN. To this end, streptozotocin-induced C57BL/6 wild-type (WT) diabetic mice were treated with SRT2104, for 24 weeks. To determine whether SRT2104 acted through inhibition of P53 - a substrate of SIRT1, the P53 activator nutlin3a was administered to the WT diabetic mice in the presence of SRT2104. In order to test whether nuclear factor erythroid 2-related factor 2 (NRF2) - the master of cellular antioxidants - mediated SIRT1 and P53's actions, WT and Nrf2 gene knockout (KO) diabetic mice were treated with SRT2104 or the P53 inhibitor pifithrin-α (PFT-α). In the WT mice, SRT2104 enhanced renal SIRT1 expression and activity, deacetylated P53, and activated NRF2 antioxidant signaling, providing remarkable protection against the DM-induced renal oxidative stress, inflammation, fibrosis, glomerular remodeling and albuminuria. These effects were completely abolished in the presence of nutlin3a. Deletion of the Nrf2 gene completely abrogated the efficacies of SRT2104 and PFT-α in elevating antioxidants and ameliorating DN, despite their abilities to activate SIRT1 and inhibit P53 in the Nrf2 KO mice. The present study reports the beneficial effects of SRT2104 on DN, uncovering a SIRT1/P53/NRF2 pathway that modulates the pathogenesis of DN.

Sirtuin activators and inhibitors

Sirtuins 1-7 (SIRT1-7) belong to the third class of deacetylase enzymes, which are dependent on NAD(+) for activity. Sirtuins activity is linked to gene repression, metabolic control, apoptosis and cell survival, DNA repair, development, inflammation, neuroprotection, and healthy aging. Because sirtuins modulation could have beneficial effects on human diseases there is a growing interest in the discovery of small molecules modifying their activities. We review here those compounds known to activate or inhibit sirtuins, discussing the data that support the use of sirtuin-based therapies. Almost all sirtuin activators have been described only for SIRT1. Resveratrol is a natural compound which activates SIRT1, and may help in the treatment or prevention of obesity, and in preventing tumorigenesis and the aging-related decline in heart function and neuronal loss. Due to its poor bioavailability, reformulated versions of resveratrol with improved bioavailability have been developed (resVida, Longevinex(®) , SRT501). Molecules that are structurally unrelated to resveratrol (SRT1720, SRT2104, SRT2379, among others) have been also developed to stimulate sirtuin activities more potently than resveratrol. Sirtuin inhibitors with a wide range of core structures have been identified for SIRT1, SIRT2, SIRT3 and SIRT5 (splitomicin, sirtinol, AGK2, cambinol, suramin, tenovin, salermide, among others). SIRT1 inhibition has been proposed in the treatment of cancer, immunodeficiency virus infections, Fragile X mental retardation syndrome and for preventing or treating parasitic diseases, whereas SIRT2 inhibitors might be useful for the treatment of cancer and neurodegenerative diseases.

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds

The sirtuins (SIRT1-7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacylases with remarkable abilities to prevent diseases and even reverse aspects of ageing. Mice engineered to express additional copies of SIRT1 or SIRT6, or treated with sirtuin-activating compounds (STACs) such as resveratrol and SRT2104 or with NAD+ precursors, have improved organ function, physical endurance, disease resistance and longevity. Trials in non-human primates and in humans have indicated that STACs may be safe and effective in treating inflammatory and metabolic disorders, among others. These advances have demonstrated that it is possible to rationally design molecules that can alleviate multiple diseases and possibly extend lifespan in humans.

Progesterone Attenuates SIRT1-Deficiency-Mediated Pre-Eclampsia

Pre-eclampsia is a severe hypertensive disorder of pregnancy (HDP), mainly characterized by new-onset hypertension with proteinuria after 20-week gestation. Sirtuin1 (SIRT1), a class III histone deacetylase, is associated with the regulation of various pathophysiological processes, including inflammation, immune response, metabolism, and autophagy. However, the effect of SIRT1 in the pathogenesis of pre-eclampsia remains to be elucidated. In this study, we found that the expression of SIRT1 was relatively lower in the placentas and serum samples of pre-eclampsia patients. Typical pre-eclampsia-like symptoms, such as hypertension, proteinuria, fetal growth restriction, kidney injury, and a narrow placental labyrinth layer, were observed in SIRT1 knockdown (SIRT1+/-) mice. Of note, these performances could be improved after the intraperitoneal injection of SIRT1 agonist SRT2104. More importantly, we found that the efficacy of progesterone on attenuating symptoms of PE was profoundly better than that of metformin in SIRT1+/- mice. In addition, our results suggested that progesterone can promote the invasion and inhibit the apoptosis of trophoblasts. These data suggest that SIRT1 plays an important role in pre-eclampsia and that progesterone alleviates pre-eclampsia-like symptoms mediated by SIRT1 deficiency.

SIRT1 activation attenuates cardiac fibrosis by endothelial-to-mesenchymal transition

Endothelial-to-mesenchymal transition (EndMT) is closely related to the pathogenesis of various diseases, including cardiac fibrosis. Transforming growth factor (TGF)-β1 strongly induces EndMT, and sirtuin 1 (SIRT1) may play vital roles in TGF-β/Smad pathway inhibition. This study aimed to determine whether SIRT1 activation inhibits EndMT, thereby attenuating cardiac fibrosis. Cardiac fibrosis was induced in C57BL/6 mice by subcutaneously injecting isoproterenol. SIRT1 was activated and then suppressed by intraperitoneally injecting resveratrol (RSV) and EX527, respectively. EndMT was induced by adding TGF-β1 to H5V cells and measured by immunofluorescence and western blot. The role of SIRT1 in EndMT was determined by lentivirus-mediated overexpression of SIRT1. Interactions between SIRT1 and Smad2/3 in the TGF-β/Smad2/3 pathway were examined by immunoprecipitation. SIRT1 activation upregulated CD31 and vascular endothelial-cadherin, and downregulated α-smooth muscle actin, fibroblast-specific protein 1, and vimentin. SIRT1 upregulated and EX527 inhibited TGF-β receptor 1 (TGF-βR1) and P-Smad2/3 expression, respectively. SIRT1 activation and overexpression by RSV/SRT2104 and lentivirus transfection, respectively, reduced TGF-β1-induced EndMT. SIRT1 and Smad2/3 interaction was shown by immunoprecipitation in vivo and in vitro. TGF-βR1 and P-Smad2/3 expression was downregulated and Smad2/3 nuclear translocation was inhibited. In conclusion, SIRT1 activated by RSV attenuated isoproterenol-induced cardiac fibrosis by regulating EndMT via the TGF-β/Smad2/3 pathway.