16F16
目录号 : GC46451
A PDI inhibitor
Cas No.:922507-80-0
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
16F16 is a protein disulfide isomerase (PDI) inhibitor.1 It inhibits PDI reductase activity in an enzyme assay when used at concentrations ranging from 1 to 100 µg/ml.1 16F16 reduces PC12 cell apoptosis induced by the misfolded huntingtin protein HTTQ103. It suppresses PDI-dependent mitochondrial outer membrane permeabilization (MOMP) in isolated PC12 cell mitochondria. 16F16 (2, 3, 4, and 10 µM) reduces HTTN90Q73 mutant huntingtin-induced medium spinal neuron death and MOMP in rat corticostriatal slices. It also reduces pyramidal neuron death induced by amyloid-β precursor protein (APP) in rat corticostriatal slices.
1.Hoffstrom, B.G., Kaplan, A., Letso, R., et al.Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteinsNat. Chem. Biol.6(12)900-906(2010)
| Cas No. | 922507-80-0 | SDF | |
| Canonical SMILES | O=C(CCl)N1C(C(OC)=O)(C)C2=C(C(C=CC=C3)=C3N2)CC1 | ||
| 分子式 | C16H17ClN2O3 | 分子量 | 320.8 |
| 溶解度 | DMSO: 10 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 | 3.1172 mL | 15.586 mL | 31.1721 mL |
| 5 mM | 0.6234 mL | 3.1172 mL | 6.2344 mL |
| 10 mM | 0.3117 mL | 1.5586 mL | 3.1172 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。
Inhibitor for protein disulfide-isomerase family A member 3 enhances the antiproliferative effect of inhibitor for mechanistic target of rapamycin in liver cancer: An in vitro study on combination treatment with everolimus and 16F16
Oncol Lett 2021 Jan;21(1):28.PMID:33240434DOI:10.3892/ol.2020.12289.
mTOR is involved in the proliferation of liver cancer. However, the clinical benefit of treatment with mTOR inhibitors for liver cancer is controversial. Protein disulfide isomerase A member 3 (PDIA3) is a chaperone protein, and it supports the assembly of mTOR complex 1 (mTORC1) and stabilizes signaling. Inhibition of PDIA3 function by a small molecule known as 16F16 may destabilize mTORC1 and enhance the effect of the mTOR inhibitor everolimus (Ev). The aim of the present study was to elucidate the usefulness of combination treatment with Ev and 16F16 in liver cancer using cultured Li-7 and HuH-6 cells. The proliferation of cultured cells was examined following treatment with 0.01 µM Ev, 2 µM 16F16 or both. The expression levels and phosphorylation of S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) were examined by western blotting. Li-7 was susceptible to Ev, and proliferation was reduced to 69.5±7.2% by Ev compared with that of untreated cells. Proliferation was reduced to 90.2±10.8% by 16F16 but to 62.3±12.2% by combination treatment with Ev and 16F16. HuH-6 cells were resistant to Ev, and proliferation was reduced to 86.7±6.1% by Ev and 86.6±4.8% by 16F16. However, combination treatment suppressed proliferation to 57.7±4.0%. Phosphorylation of S6K was reduced by Ev in both Li-7 and HuH-6 cells. Phosphorylation of 4E-BP1 was reduced by combination treatment in both Li-7 and HuH-6 cells. Immunoprecipitation assays demonstrated that PDIA3 formed a complex with 4E-BP1 but not with S6K. The small molecule 16F16 increased susceptibility to Ev in cultured liver cancer cells, which are resistant to Ev. The inhibition was associated with reduction of 4E-BP1 phosphorylation, which formed a complex with PDIA3. Combination treatment with Ev and 16F16 could be a novel therapeutic strategy for liver cancer.
A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRER axis
Cell Death Differ 2022 Sep;29(9):1769-1789.PMID:35301432DOI:10.1038/s41418-022-00963-8.
Hypoxic tumor microenvironment (TME) plays critical roles in induction of cancer stem cell-like phenotype in breast cancer and contribute to chemoresistance. However, the mechanism underlying stemness reprogramming of breast cancer cells (BCs) by hypoxic TME remains largely unknown. In the present study, we illustrated that HIF-2α, but not HIF-1α, induces stemness in BCs under hypoxia through SOD2-mtROS-PDI/GRP78-UPRER pathway, linking mitochondrial metabolic state to endoplasmic reticulum (ER) response via mitochondrial reactive oxygen species (mtROS) level. HIF-2α activates endoplasmic reticulum unfolded protein response (UPRER) in drug-sensitive MCF7 and T47D cells to induce drug-resistant stem-like phenotype. Genetic depletion or pharmacological inhibition (YQ-0629) of HIF-2α abolished hypoxia-induced stem-like phenotype in vitro and in vivo. Mechanistically, HIF-2α activates transcription of superoxide dismutase 2 (SOD2) under hypoxia and thereby decreases mtROS level. With less mtROS transported to endoplasmic reticulum, the expression and activity of protein disulfide isomerase (PDI) is suppressed, allowing glucose-regulated protein 78 (GRP78) to dissociate from receptor proteins of UPRER and bind misfolded protein to activate UPRER, which eventually confer chemoresistance and stem-like properties to BCs. Moreover, the increase in mtROS and PDI levels caused by HIF-2α knockdown and the subsequent UPRER inhibition could be substantially rescued by mitoTEMPOL (a mtROS scavenger), 16F16 (a PDI inhibitor), or GRP78 overexpression. Overall, we reported the critical roles of HIF-2α-SOD2-mtROS-PDI/GRP78-UPRER axis in mediating hypoxia-induced stemness in BCs, highlighting the interaction between organelles and providing evidence for further development of targeted HIF-2α inhibitor as a promising therapeutic strategy for chemoresistant breast cancer.
Host oxidative folding pathways offer novel anti-chikungunya virus drug targets with broad spectrum potential
Antiviral Res 2017 Jul;143:246-251.PMID:28461071DOI:10.1016/j.antiviral.2017.04.014.
Alphaviruses require conserved cysteine residues for proper folding and assembly of the E1 and E2 envelope glycoproteins, and likely depend on host protein disulfide isomerase-family enzymes (PDI) to aid in facilitating disulfide bond formation and isomerization in these proteins. Here, we show that in human HEK293 cells, commercially available inhibitors of PDI or modulators thereof (thioredoxin reductase, TRX-R; endoplasmic reticulum oxidoreductin-1, ERO-1) inhibit the replication of CHIKV chikungunya virus (CHIKV) in vitro in a dose-dependent manner. Further, the TRX-R inhibitor auranofin inhibited Venezuelan equine encephalitis virus and the flavivirus Zika virus replication in vitro, while PDI inhibitor 16F16 reduced replication but demonstrated notable toxicity. 16F16 significantly altered the viral genome: plaque-forming unit (PFU) ratio of CHIKV in vitro without affecting relative intracellular viral RNA quantities and inhibited CHIKV E1-induced cell-cell fusion, suggesting that PDI inhibitors alter progeny virion infectivity through altered envelope function. Auranofin also increased the extracellular genome:PFU ratio but decreased the amount of intracellular CHIKV RNA, suggesting an alternative mechanism of action. Finally, auranofin reduced footpad swelling and viremia in the C57BL/6 murine model of CHIKV infection. Our results suggest that targeting oxidative folding pathways represents a potential new anti-alphavirus therapeutic strategy.
Expression of membrane protein disulphide isomerase A1 (PDIA1) disrupt a reducing microenvironment in endometrial epithelium for embryo implantation
Exp Cell Res 2021 Aug 15;405(2):112665.PMID:34111473DOI:10.1016/j.yexcr.2021.112665.
Various proteins in the endometrial epithelium are differentially expressed in the receptive phase and play a pivotal role in embryo implantation. The Protein Disulphide Isomerase (PDI) family contains 21 members that function as chaperone proteins through their redox activities. Although total PDIA1 protein expression was high in four common receptive (Ishikawa and RL95-2) and non-receptive (HEC1-B and AN3CA) endometrial epithelial cell lines, significantly higher membrane PDIA1 expression was found in non-receptive AN3CA cells. In Ishikawa cells, oestrogen up-regulated while progesterone down-regulated membrane PDIA1 expression. Moreover, mid-luteal phase hormone treatment down-regulated membrane PDIA1 expression. Furthermore, oestrogen at 10 nM reduced spheroid attachment on Ishikawa cells. Interestingly, inhibition of PDIA1 function by bacitracin or 16F16 increased the spheroid attachment rate onto non-receptive AN3CA cells. Over-expression of PDIA1 in receptive Ishikawa cells reduced the spheroid attachment rate and significantly down-regulated integrin β3 levels, but not integrin αV and E-cadherin. Addition of reducing agent TCEP induced a sulphydryl-rich microenvironment and increased spheroid attachment onto AN3CA cells and human primary endometrial epithelial cells collected at LH+7/8 days. The luminal epithelial cells from human endometrial biopsies had higher PDIA1 protein expression in the proliferative phase than in the secretory phase. Our findings suggest oestrogen and progesterone regulate PDIA1 expression, resulting in the differential expressions of membrane PDIA1 protein to modulate endometrial receptivity. This suggests that membrane PDIA1 expression prior to embryo transfer could be used to predict endometrial receptivity and embryo implantation in women undergoing assisted reproduction treatment.
Design, synthesis and evaluation of protein disulfide isomerase inhibitors with nitric oxide releasing activity
Bioorg Med Chem Lett 2020 Feb 1;30(3):126898.PMID:31874828DOI:10.1016/j.bmcl.2019.126898.
Protein disulfide isomerase (PDI), a chaperone protein mostly in endoplasmic reticulum, catalyzes disulfide bond breakage, formation, and rearrangement to promote protein folding. PDI is regarded as a new target for treatment of several disorders. Here, based on the combination principle, we report a new PDI reversible modulator 16F16A-NO by replacing the reactive group in a known PDI inhibitor 16F16 with nitric oxide (NO) donor. Using molecular docking experiment, 16F16A-NO could embed into the active cavity of PDI. From newly developed fluorescent assay, 16F16A-NO showed rapid NO release. Furthermore, it is capable to moderately inhibit activity of PDI and S-nitrosylate the protein, indicating by insulin aggregation assay and biotin-switch technique. Finally, it displayed a dose-dependent antiproliferative activity against SH-SY5Y and HeLa tumor cells. Our designed hybrid compound 16F16A-NO showed a reasonable activity and might offer a promising avenue to develop novel PDI inhibitors for disease treatments.