TIQ-A
目录号 : GC45057
A PARP1 inhibitor
Cas No.:420849-22-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Poly(ADP-ribose) polymerase 1 (PARP1) is a critical DNA repair enzyme involved in DNA single-strand break repair via the base excision repair pathway. PARP1 is triggered by DNA damage and its excessive activation has been proposed as a causative factor in many pathological conditions including ischemia and reperfusion injury, asthma-related inflammation, and atherogenesis. TIQ-A is a PARP1 inhibitor (IC50 = 450 nM in cultured mouse cortical neurons). It displays neuroprotective effects in cultured mouse cortical neurons injured by oxygen-glucose deprivation (IC50 = 0.15 µM). TIQ-A has been used to inhibit eosinophilic infiltration into airways of OVA-challenged mice and to induce the regression of atherosclerotic plaques in high-fat fed apolipoprotein E(-/-) mice.
| Cas No. | 420849-22-5 | SDF | |
| Canonical SMILES | O=C1NC2=C(C=CS2)C3=C1C=CC=C3 | ||
| 分子式 | C11H7NOS | 分子量 | 201.2 |
| 溶解度 | DMF: 15 mg/ml,DMF:PBS (pH 7.2) (1:8): 0.1 mg/ml,DMSO: 10 mg/ml,Ethanol: 0.5 mg/ml | 储存条件 | Store at -20°C |
| 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。 |
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| 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 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 4.9702 mL | 24.8509 mL | 49.7018 mL |
| 5 mM | 0.994 mL | 4.9702 mL | 9.9404 mL |
| 10 mM | 0.497 mL | 2.4851 mL | 4.9702 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。
Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs
Bioorg Med Chem 2021 Dec 15;52:116511.PMID:34801828DOI:10.1016/j.bmc.2021.116511.
The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.
Derivatives of a PARP Inhibitor TIQ-A through the Synthesis of 8-Alkoxythieno[2,3- c]isoquinolin-5(4 H)-ones
ACS Omega 2020 May 28;5(22):13447-13453.PMID:32548533DOI:10.1021/acsomega.0c01879.
Thieno[2,3-c]isoquinolin-5(4H)-one is known for its potential as an anti-ischemic agent through the inhibition of poly(ADP-ribose) polymerase 1 (PARP1). However, the compound also inhibits many other enzymes of the PARP family, potentially limiting its usability. The broad inhibition profile, on the other hand, indicates that this molecule backbone could be potentially used as a scaffold for the development of specific inhibitors for certain PARP enzymes. These efforts call for novel synthetic strategies for substituted thieno[2,3-c]isoquinolin-5(4H)-one that could provide the needed selectivity. In this article, an efficient synthetic strategy for 8-alkoxythieno[2,3-c]isoquinolin-5(4H)-ones through eight steps is presented and other tested synthetic pathways are discussed in detail. Synthesis of 7-methoxythieno[2,3-c]isoquinolin-5(4H)-one is also demonstrated to show that the strategy can be applied widely in the syntheses of substituted alkoxythieno[2,3-c]isoquinolin-5(4H)-ones.
PARP-1-regulated TNF-α expression in the dorsal root ganglia and spinal dorsal horn contributes to the pathogenesis of neuropathic pain in rats
Brain Behav Immun 2020 Aug;88:482-496.PMID:32283287DOI:10.1016/j.bbi.2020.04.019.
Emerging evidence has implicated poly-(ADP-ribose) polymerase 1 (PARP-1), a transcriptional coregulator, in a variety of inflammatory diseases. In the current study, the role of PARP-1 in neuropathic pain and the underlying mechanisms were investigated. Neuropathic pain was determined by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) following lumbar 5 spinal nerve ligation (SNL) in male rates. Western blotting, qRT-PCR, immunohistochemistry, chromatin immunoprecipitation (ChIP), and Co-IP assays were performed to elucidate the mechanisms. The results showed that SNL resulted in a significant increase in the expression and activation of PARP-1 in the ipsilateral L4/5 dorsal root ganglia (DRG) and spinal dorsal horn, which occurred on day one, reached peak on day 7, and persisted more than 2 weeks after surgery. Double immunofluorescence staining revealed that PARP-1 was expressed exclusively in DRG A-type and C-type neurons. In the spinal cord, PARP-1 mainly colocalized with the neuronal marker NeuN and the astrocytic marker GFAP specifically in the superficial lamina. Prior intrathecal (i.t.) injection of PJ-34, a PARPs inhibitor, or TIQ-A, a specific PARP-1 inhibitor, dose-dependently prevented the reductions in PWT and PWL following SNL. Established neuropathic pain-like hypersensitivity was also attenuated with i.t. injection of PJ-34 and TIQ-A starting on day 7 following SNL, a timepoint at which neuropathic pain was fully established. SNL-induced mechanical allodynia and thermal hyperalgesia were also alleviated by i.t. injection of PARP-1 siRNA following a reduction in PARP-1 expression in the dorsal horn. Moreover, the SNL-induced increases in TNF-α protein and mRNA in the dorsal horn and DRG were dramatically suppressed by i.t. injection of TIQ-A or PARP-1 siRNA. The i.t. lipopolysaccharide (LPS)-induced increase in the production of TNF-α in the dorsal horn was also inhibited by prior to i.t. injection of PARP-1 siRNA. Results of ChIP assay showed that SNL-induced PARP-1 activation promoted the binding of NF-κB p65 with the TNF-α promoter in the dorsal horn and that PARP-1 inhibition reduced this binding and suppressed TNF-α expression. Co-IP assay revealed that SNL caused a significant increase in the level of histone H1 poly(ADP)-ribosylation. Together, these results indicate that PARP-1-regulated TNF-α expression in the DRG and spinal dorsal horn following SNL contributes to the development and maintenance of neuropathic pain. Targeting PARP-1 might be a promising therapeutic strategy for the treatment of the chronic pain.
Thieno[2,3-c]isoquinolin-5-one, a potent poly(ADP-ribose) polymerase inhibitor, promotes atherosclerotic plaque regression in high-fat diet-fed apolipoprotein E-deficient mice: effects on inflammatory markers and lipid content
J Pharmacol Exp Ther 2009 Apr;329(1):150-8.PMID:19124646DOI:10.1124/jpet.108.145938.
We recently showed that poly(ADP-ribose) polymerase (PARP) is activated within atherosclerotic plaques in an animal model of atherosclerosis. Pharmacological inhibition of PARP or reduced expression in heterozygous animals interferes with atherogenesis and may promote factors of plaque stability, possibly reflecting changes in inflammatory and cellular factors consistent with plaque stability. The current study addresses the hypothesis that pharmacological inhibition of PARP promotes atherosclerotic plaque regression. Using a high-fat diet-induced atherosclerosis apolipoprotein E(-/-) mouse model, we demonstrate that administration of the potent PARP inhibitor, thieno[2,3-c]isoquinolin-5-one (TIQ-A), when combined with a regular diet regimen during treatment, induced regression of established plaques. Plaque regression was associated with a reduction in total cholesterol and low-density lipoproteins. Furthermore, plaques of TIQ-A-treated mice were highly enriched with collagen and smooth muscle cells, displayed thick fibrous caps, and exhibited a marked reduction in CD68-positive macrophage recruitment and associated foam cell presence. These changes correlated with a significant decrease in expression of monocyte chemoattractant protein-1 and intercellular cell adhesion molecule-1, potentially as a result of a robust reduction in tumor necrosis factor expression. The PARP inhibitor appeared to affect cholesterol metabolism by affecting acyl-coenzymeA/cholesterol acyltransferase-1 expression but exerted no effect on cholesterol influx or efflux as assessed by an examination of the ATP-binding cassette transporter-1 and the scavenger receptor-A expression levels in the different experimental groups. In accordance, PARP inhibition may prove beneficial not only in preventing atherogenesis but also in promoting regression of preexisting plaques.
Poly(ADP-ribose) polymerase-1 inhibition prevents eosinophil recruitment by modulating Th2 cytokines in a murine model of allergic airway inflammation: a potential specific effect on IL-5
J Immunol 2006 Nov 1;177(9):6489-96.PMID:17056581DOI:10.4049/jimmunol.177.9.6489.
We recently used a murine model of allergic airway inflammation to show that poly(ADP-ribose) polymerase-1 (PARP-1) plays an important role in the pathogenesis of asthma-related lung inflammation. In this study, we show that PARP-1 inhibition, by a novel inhibitor (TIQ-A) or by gene deletion, prevented eosinophilic infiltration into the airways of OVA-challenged mice. Such impairment of eosinophil recruitment appeared to take place after IgE production. OVA challenge of wild-type mice resulted in a significant increase in IL-4, IL-5, IL-10, IL-13, and GM-CSF secretions. Although IL-4 production was moderately affected in OVA-challenged PARP-1(-/-) mice, the production of IL-5, IL-10, IL-13, and GM-CSF was completely inhibited in ex vivo OVA-challenged lung cells derived from these animals. A single TIQ-A injection before OVA challenge in wild-type mice mimicked the latter effects. The marked effect PARP-1 inhibition exerted on mucus production corroborated the effects observed on the Th2 response. Although PARP-1 inhibition by gene knockout increased the production of the Th1 cytokines IL-2 and IL-12, the inhibition by TIQ-A exerted no effect on these two cytokines. The failure of lung cells derived from OVA-challenged PARP-1(-/-) mice to synthesize GM-CSF, a key cytokine in eosinophil recruitment, was reestablished by replenishment of IL-5. Furthermore, intranasal administration of IL-5 restored the impairment of eosinophil recruitment and mucus production in OVA-challenged PARP-1(-/-) mice. The replenishment of either IL-4 or IgE, however, did not result in such phenotype reversals. Altogether, these results suggest that PARP-1 plays a critical role in eosinophil recruitment by specifically regulating the cascade leading to IL-5 production.