Syrosingopine
(Synonyms: 乙酯利血平,Su 3118) 目录号 : GC39536
Syrosingopine (Su-3118) is a dual MCT1 and MCT4 inhibitor with IC50 values of 2500nM and 40 nM in HAP1 cells, respectively.
Cas No.:84-36-6
Sample solution is provided at 25 µL, 10mM.
;)
,-1-7$$$37316672.jpg');)
;)
;)
$$$36806353.jpg');)
;33(7)%EF%BC%9A546-561$$$37156877.jpg');)
;)
;)
;)
%201124-1138.$$$35908550.jpg');)
%20766-780.$$$37100057.jpg');)
%20418-432.$$$36893736.jpg');)
%EF%BC%9A-240-255.$$$35108512.jpg');)
533-545$$$36543525.jpg');)
%201-13.$$$36600053.jpg');)
;)
Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Syrosingopine (Su-3118) is a dual MCT1 and MCT4 inhibitor with IC50 values of 2500nM and 40 nM in HAP1 cells, respectively.
Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase by inhibiting the Lactate Transporters MCT1 and MCT4. The loss of NAD+ regeneration capacity due to combined metformin and syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. [1]
Syrosingopine treatment leads to reduced serum lactate levels significantlyn, and higher intracellular lactate from liver tumor nodules in syrosingopine-treated liver tumor model mice. [1]
[1] Don Benjamin, et al. Cell Rep. 2018 Dec 11;25(11):3047-3058.e4.
| Cas No. | 84-36-6 | SDF | |
| 别名 | 乙酯利血平,Su 3118 | ||
| Canonical SMILES | [H][C@@]12C(NC3=C4C=CC(OC)=C3)=C4CCN1C[C@]5(C[C@@H](OC(C6=CC(OC)=C(OC(OCC)=O)C(OC)=C6)=O)[C@H](OC)[C@@H](C(OC)=O)[C@]5(C2)[H])[H] | ||
| 分子式 | C35H42N2O11 | 分子量 | 666.71 |
| 溶解度 | DMSO: 62.5 mg/mL (93.74 mM) | 储存条件 | Store at -20°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
||
| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
 |
1 mg | 5 mg | 10 mg |
| 1 mM | 1.4999 mL | 7.4995 mL | 14.999 mL |
| 5 mM | 0.3 mL | 1.4999 mL | 2.9998 mL |
| 10 mM | 0.15 mL | 0.75 mL | 1.4999 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Dual Inhibition of the Lactate Transporters MCT1 and MCT4 Is Synthetic Lethal with Metformin due to NAD+ Depletion in Cancer Cells
Cell Rep 2018 Dec 11;25(11):3047-3058.e4.PMID:30540938DOI:10.1016/j.celrep.2018.11.043.
Highly glycolytic cancer cells prevent intracellular acidification by excreting the glycolytic end-products lactate and H+ via the monocarboxylate transporters 1 (MCT1) and 4 (MCT4). We report that Syrosingopine, an anti-hypertensive drug, is a dual MCT1 and MCT4 inhibitor (with 60-fold higher potency on MCT4) that prevents lactate and H+ efflux. Syrosingopine elicits synthetic lethality with metformin, an inhibitor of mitochondrial NADH dehydrogenase. NAD+, required for the ATP-generating steps of glycolysis, is regenerated from NADH by mitochondrial NADH dehydrogenase or lactate dehydrogenase. Syrosingopine treatment leads to high intracellular lactate levels and thereby end-product inhibition of lactate dehydrogenase. The loss of NAD+ regeneration capacity due to combined metformin and Syrosingopine treatment results in glycolytic blockade, leading to ATP depletion and cell death. Accordingly, ATP levels can be partly restored by exogenously provided NAD+, the NAD precursor nicotinamide mononucleotide (NMN), or vitamin K2. Thus, pharmacological inhibition of MCT1 and MCT4 combined with metformin treatment is a potential cancer therapy.
Syrosingopine sensitizes cancer cells to killing by metformin
Sci Adv 2016 Dec 23;2(12):e1601756.PMID:28028542DOI:10.1126/sciadv.1601756.
We report that the anticancer activity of the widely used diabetic drug metformin is strongly potentiated by Syrosingopine. Synthetic lethality elicited by combining the two drugs is synergistic and specific to transformed cells. This effect is unrelated to Syrosingopine's known role as an inhibitor of the vesicular monoamine transporters. Syrosingopine binds to the glycolytic enzyme α-enolase in vitro, and the expression of the γ-enolase isoform correlates with nonresponsiveness to the drug combination. Syrosingopine sensitized cancer cells to metformin and its more potent derivative phenformin far below the individual toxic threshold of each compound. Thus, combining Syrosingopine and codrugs is a promising therapeutic strategy for clinical application for the treatment of cancer.
Evaluation of Syrosingopine, an MCT Inhibitor, as Potential Modulator of Tumor Metabolism and Extracellular Acidification
Metabolites 2022 Jun 17;12(6):557.PMID:35736489DOI:10.3390/metabo12060557.
Extracellular acidification has been shown to be an important characteristic of invasive tumors, as it promotes invasion and migration but also resistance to treatments. Targeting transporters involved in the regulation of tumor pH constitutes a promising anti-tumor approach, as it would disrupt cellular pH homeostasis and negatively impact tumor growth. In this study, we evaluated the impact of Syrosingopine, an inhibitor of MCT1 and MCT4, as a modulator of tumor metabolism and extracellular acidification in human breast cancer (MDA-MB-231) and pharyngeal squamous cell carcinoma (FaDu) cell models. In both models in vitro, we observed that exposure to Syrosingopine led to a decrease in the extracellular acidification rate, intracellular pH, glucose consumption, lactate secretion and tumor cell proliferation with an increase in the number of late apoptotic/necrotic cells. However, in vivo experiments using the MDA-MB-231 model treated with a daily injection of Syrosingopine did not reveal any significant change in extracellular pH (pHe) (as measured using CEST-MRI) or primary tumor growth. Overall, our study suggests that targeting MCT could lead to profound changes in tumor cell metabolism and proliferation, and it warrants further research to identify candidates without off-target effects.
Metformin confers sensitisation to Syrosingopine in multiple myeloma cells by metabolic blockage and inhibition of protein synthesis
J Pathol 2023 Feb 18.PMID:36807305DOI:10.1002/path.6066.
Multiple myeloma (MM) remains an incurable haematological malignancy despite substantial advances in therapy. Hypoxic bone marrow induces metabolic rewiring in MM cells contributing to survival and drug resistance. Therefore, targeting metabolic pathways may offer an alternative treatment option. In this study, we repurpose two FDA-approved drugs, Syrosingopine and metformin. Syrosingopine was used as a dual inhibitor of monocarboxylate transporter 1 and 4 (MCT1/4) and metformin as an inhibitor for oxidative phosphorylation (OXPHOS). Anti-tumour effects were evaluated for single agents and in combination therapy. Survival and expression data for MCT1/MCT4 were obtained from the Total Therapy 2, Mulligan, and Multiple Myeloma Research Foundation cohorts. Cell death, viability, and proliferation were measured using Annexin V/7-AAD, CellTiterGlo, and BrdU, respectively. Metabolic effects were assessed using Seahorse Glycolytic Rate assays and LactateGlo assays. Differential protein expression was determined using western blotting, and the SUnSET method was implemented to quantify protein synthesis. Finally, the syngeneic 5T33MMvv model was used for in vivo analysis. High-level expression of MCT1 and MCT4 both correlated with a significantly lower overall survival of patients. Lactate production as well as MCT1/MCT4 expression were significantly upregulated in hypoxia, confirming the Warburg effect in MM. Dual inhibition of MCT1/4 with Syrosingopine resulted in intracellular lactate accumulation and reduced cell viability and proliferation. However, only at higher doses (>10 μm) was Syrosingopine able to induce cell death. By contrast, combination treatment of Syrosingopine with metformin was highly cytotoxic for MM cell lines and primary patient samples and resulted in a suppression of both glycolysis and OXPHOS. Moreover, pathway analysis revealed an upregulation of the energy sensor p-AMPKα and more downstream a reduction in protein synthesis. Finally, the combination treatment resulted in a significant reduction in tumour burden in vivo. This study proposes an alternative combination treatment for MM and provides insight into intracellular effects. © 2023 The Pathological Society of Great Britain and Ireland.
Selective depleting effect of Syrosingopine on brain catecholamine levels with relation to morphine analgesia in the rat
Pharmacol Biochem Behav 1976 Apr;4(4):419-25.PMID:6976DOI:10.1016/0091-3057(76)90058-7.
Reserpine was the most potent, rescinnamine the next and Syrosingopine the weakest in the depleting effects on brain amines of rauwolfia alkaloids. After Syrosingopine, brain dopamine (DA) was decreased to a smaller degree and with a shorter duration as compared with norepinephrine (NE) and serotonin (5-HT), whereas reserpine elicited a marked and long lasting reduction in these amines. Accordingly, Syrosingopine induced a depletion of brain NE and 5-HT without alteration in brain DA content 2-4 days after administration. Repeated administrations of Syrosingopine, 2 mg/kg daily for 2 or 4 days, resulted in similar alterations in brain amine levels. This selective depleting effect of Syrosingopine on brain amines was potentiated by combined treatment with disulfiram or fusaric acid, a dopamine beta-hydroxylase inhibitor. Under the condition of selective depletion of brain amines induced by repeated administrations of Syrosingopine, 2 mg/kg daily for 2 days, the analgesic action of morphine was not affected, whereas reserpine and tetrabenazine antagonized morphine analgesia, concomitant with inducing a depletion of all brain amines. The results suggest that brain DA may be more important than brain NE or 5-HT with regard to the mechanisms by which morpine produces analgesia.