C2-8
(Synonyms: Polyglutamine Aggregation Inhibitor III) 目录号 : GC43079
An inhibitor of polyQ aggregation
Cas No.:300670-16-0
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
C2-8 is an inhibitor of polyglutamine (polyQ) aggregation (IC50s = 25 and 0.05 μM for recombinant HDQ51 and in PC12 cells, respectively). It also inhibits polyQ aggregation in organotypic hippocampal slice cultures isolated from R6/2 transgenic mice and reduces neurodegeneration in a dose-dependent manner in a Drosophila model of Huntington's disease. C2-8 (100 and 200 mg/kg) reduces huntingtin aggregate size, reduces neuronal atrophy, and improves motor performance in a rotarod test in the R6/2 transgenic mouse model of Huntington's disease.
| Cas No. | 300670-16-0 | SDF | |
| 别名 | Polyglutamine Aggregation Inhibitor III | ||
| Canonical SMILES | BrC1=CC=C(NC(C2=CC=CC(S(NC3=CC=C(Br)C=C3)(=O)=O)=C2)=O)C=C1 | ||
| 分子式 | C19H14Br2N2O3S | 分子量 | 510.2 |
| 溶解度 | DMF: 33 mg/ml,DMSO: 33 mg/ml,DMSO:PBS(pH 7.2) (1:3): 0.25 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 | 1.96 mL | 9.8001 mL | 19.6002 mL |
| 5 mM | 0.392 mL | 1.96 mL | 3.92 mL |
| 10 mM | 0.196 mL | 0.98 mL | 1.96 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。
An independent study of the preclinical efficacy of C2-8 in the R6/2 transgenic mouse model of Huntington's disease
J Huntingtons Dis 2013;2(4):443-51.PMID:25062731DOI:10.3233/JHD-130074.
Background: C2-8 is a small molecule inhibitor of polyglutamine aggregation and can reduce photoreceptor neurodegeneration in a Drosophila model of Huntington's disease (HD). Further preclinical studies have shown that oral administration of C2-8 in R6/2 HD transgenic mice can penetrate into the brain, reduce mHTT-exon1 aggregation, improve motor performance and diminish striatal neuron atrophy. Objective: In this independent preclinical study, we aimed to evaluate the pharmacokinetic properties and therapeutic efficacy of C2-8 intraperitoneal (IP) delivery in the R6/2 HD mouse. Methods: R6/2 mice were IP injected with low dose C2-8 (10 mg/kg), high dose C2-8 (20 mg/kg), or vehicle twice daily from 3 weeks to 3 months old. Longitudinal behavioral tests (accelerating Rotarod and wire-hang) were performed to evaluate the motor deficits, and neuropathology was measured by unbiased stereology. Results: We confirmed that the compound has good blood-brain-barrier penetration after acute or sub-chronic intraperitoneal delivery. Chronic treatment with C2-8 in R6/2 mice results in a significant reduction of nuclear mHTT aggregate volume in the brains, replicating a key finding of C2-8 as a polyglutamine aggregation inhibitor in vivo. However, by comparing HD mice with C2-8 treatment to those with vehicle treatment, we were unable to demonstrate significant amelioration of motor deficits using Rotarod and wire-hang tests. Moreover, we did not observe improvement in the striatal neurodegenerative pathology, as measured by brain weight, striatal volume, and striatal neuron volume in the C2-8 treated R6/2 mice. Conclusions: Our study supports the practice of independent preclinical studies for novel molecules in HD therapeutic development and suggests that the use of alternative delivery strategies and full-length HD mouse models are likely needed to further assess whether the aggregate-inhibiting properties of C2-8 can be consistently translated into a preclinical benefit in HD mice.
A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse
Proc Natl Acad Sci U S A 2007 Oct 16;104(42):16685-9.PMID:17925440DOI:10.1073/pnas.0707842104.
Huntington's disease (HD) is a progressive neurodegenerative disease caused by a glutamine expansion within huntingtin protein. The exact pathological mechanisms determining disease onset and progression remain unclear. However, aggregates of insoluble mutant huntingtin (mhtt), a hallmark of HD, are readily detected within neurons in HD brain. Although aggregated polyglutamines may not be inherently toxic, they constitute a biomarker for mutant huntingtin useful for developing therapeutics. We previously reported that the small molecule, C2-8, inhibits polyglutamine aggregation in cell culture and brain slices and rescues degeneration of photoreceptors in a Drosophila model of HD. In this study, we assessed the therapeutic potential of C2-8 in the R6/2 mouse model of HD, which has been used to provide proof-of-concept data in considering whether to advance therapies to human HD. We show that, at nontoxic doses, C2-8 penetrates the blood-brain barrier and is present in brain at a high concentration. C2-8-treated mice showed improved motor performance and reduced neuronal atrophy and had smaller huntingtin aggregates. There have been no prior drug-like, non-toxic, brain-penetrable aggregation inhibitors to arise from cell-based high-throughput screens for reducing huntingtin aggregation that is efficacious in preclinical in vivo models. C2-8 provides an essential tool to help elucidate mechanisms of neurodegeneration in HD and a therapeutic lead for further optimization and development.
3-(N-arylsulfamoyl)benzamides, inhibitors of human sirtuin type 2 (SIRT2)
Bioorg Med Chem Lett 2012 Apr 15;22(8):2789-93.PMID:22446090DOI:10.1016/j.bmcl.2012.02.089.
Inhibition of sirtuin 2 (SIRT2) is known to be protective against the toxicity of disease proteins in Parkinson's and Huntington's models of neurodegeneration. Previously, we developed SIRT2 inhibitors based on the 3-(N-arylsulfamoyl)benzamide scaffold, including3-(N-(4-bromophenyl)sulfamoyl)-N-(4-bromophenyl)benzamide(C2-8, 1a), which demonstrated neuroprotective effects in a Huntington's mouse model, but had low potency of SIRT2 inhibition. Here we report that N-methylation of 1a greatly increases its potency and results in excellent selectivity for SIRT2 over SIRT1 and SIRT3 isoforms. Structure-activity relationships observed for 1a analogs and docking simulation data suggest that the para-substituted amido moiety of these compounds could occupy two potential hydrophobic binding pockets in SIRT2. These results provide a direction for the design of potent drug-like SIRT2 inhibitors.
Vital capacity in tetraplegics twenty years and beyond
Spinal Cord 2001 Mar;39(3):139-44.PMID:11326323DOI:10.1038/sj.sc.3101136.
Objectives: To observe the trends in vital capacity (VC) over time in tetraplegics 20 years and more after injury, the effects of age at injury, severity of injury and gender on this trend. Methods: The medical records of all spinal cord injured persons admitted to a regional spinal injury center from January 1960 to December 1996 were reviewed. Fifty-seven patients had documented post-rehabilitation VC (mean 1.3+/-1.1 years) and VC at 10 (mean 11.8+/-2.69) and 20 (20.60+/-2.67) years post injury and beyond. Results: The mean age at injury was 23.2+/-9.1 years. Severity of injury when classified according the system proposed by Coll et al were: Group 1: C1-4 Frankel A injury: 11.6%, Group 2: C5-8 Frankel A injury: 55.6%, Group 3: C2-8 Frankel B and C: 29.8% and Group 4: C2-8 Frankel D: 3.5% respectively. The mean VC at initial, 10 and 20 years post injury was 2586+/-948, 2803+/-940 and 2525+/-818 cc respectively. Multivariate analysis of variance revealed that there was significant difference in VC over a 20 year period, (F(2,54)=8.43, P<0.05). The difference between VC at 10 years and VC at 20 years accounted for the 19.8% of the variance in VC over time (F(1,55)=12.35, P<0.05). Age at injury, gender and severity of injury did not have a significant influence on the rate of decline in VC. Analysis of a subset of 26 patients who were followed up more than 20 years post injury (range 22 to 34.5 years) revealed similar, with a greater drop in the VC from 10 years post injury (F(1,23)=6.52, P<0.05). In this subset of patients, the mean VC at initial injury was 2840.9+/-847.3 cc, at 10 years was 2549.6+/-750.3 cc, at 20 years was 2400.9+/-724.1 cc and beyond 20 years was 2194.2+/-738.7 cc. There was no significant difference in mean VC between non smokers and ex/current smokers at initial, 10 and 20 years post injury, using the independent t-test (P>0.05). Conclusion: Vital capacity in tetraplegics declines significantly over the years, with a greater decline occurring at more than 20 years post injury.
Pharmacokinetics of obinutuzumab in Chinese patients with B-cell lymphomas
Br J Clin Pharmacol 2017 Jul;83(7):1446-1456.PMID:28072473DOI:10.1111/bcp.13232.
Aim: The Phase Ib GERSHWIN study (NCT01680991) assessed the pharmacokinetic (PK) profile of obinutuzumab following multiple intravenous (i.v.) doses to Chinese patients with B-cell lymphomas, and compared findings with previous obinutuzumab PK studies in mainly Caucasian (non-Chinese) patients. Methods: GERSHWIN was an open-label, single-arm intervention study. Patients aged >18 years with CD20+ relapsed/refractory chronic lymphocytic leukaemia (CLL), diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) were enrolled from four centres in China. The treatment period was 24 weeks; patients received obinutuzumab 1000 mg i.v. on Days (D)1, 8 and 15 of Cycle (C)1 (CLL patients: first infusion split over 2 days) and on D1 of C2-8 (all cycles: 21 days). PK parameters were estimated using non-compartmental analysis (NCA), and a population PK analysis was used to determine whether observed GERSHWIN PK data were in accordance with previous obinutuzumab PK studies in non-Chinese patients. Results: The PK analysis population included 48 patients: 28 patients completed all treatment cycles. NCA showed a similar PK profile in Chinese patients with FL, DLBCL and CLL. Steady-state concentrations of obinutuzumab appeared to be reached at the start of C2 irrespective of histology. There was no apparent relationship between body weight and systemic exposure. Most PK profiles observed in GERSHWIN lay within the 90% prediction interval of simulated profiles. Conclusions: Obinutuzumab exposure was comparable in CLL, DLBCL and FL patients. NCA and population PK analysis indicate that PK characteristics of Chinese patients with B-cell lymphomas are similar to those in non-Chinese patients.