Darinaparsin
(Synonyms: Dimethylarsinic glutathione) 目录号 : GC43379A dimethylated arsenic linked to glutathione with anticancer activities
Cas No.:69819-86-9
Sample solution is provided at 25 µL, 10mM.
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- Purity: >95.00%
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Darinaparsin is a dimethylated arsenic linked to glutathione. It is cytotoxic to DU145, LNCaP, and PC3 prostate cancer cells (IC50s = 5-10 µM) and patient-derived primary prostate cancer cells (IC50s = 2.5-20 µM), as well as Jurkat T cell lymphoma and L540 Hodgkin lymphoma cells (IC50s = 2.7 and 1.3 µM, respectively). [1][2] It decreases the tumor-initiating subpopulation in DU145 and PC3 cells and halts the cell cycle in the G2/M phase. Darinaparsin decreases transcription of Gli-2, a transcription factor that mediates Sonic hedgehog signaling, when used at a concentration of 1.5 but not 3 µM. It decreases SHP1 phosphatase activity and increases ERK phosphorylation. [2] Darinaparsin reduces tumor growth in DU145 and PC3 prostate cancer mouse xenograft models when administered at a dose of 100 mg/kg every other day.[1]
Reference:
[1]. Bansal, N., Farley, N.J., Wu, L., et al. Darinaparsin inhibits prostate tumor-initiating cells and Du145 xenografts and is an inhibitor of hedgehog signaling. Mol. Cancer Ther. 14(1), 23-30 (2015).
[2]. Ravi, D., Bhalla, S., Gartenhaus, R.B., et al. The novel organic arsenical darinaparsin induces MAPK-mediated and SHP1-dependent cell death in T-cell lymphoma and Hodgkin lymphoma cells and human xenograft models. Clin. Cancer Res. 20(23), 6023-6033 (2014).
| Cas No. | 69819-86-9 | SDF | |
| 别名 | Dimethylarsinic glutathione | ||
| 化学名 | L-γ-glutamyl-S-(dimethylarsino)-L-cysteinyl-glycine | ||
| Canonical SMILES | OC(CNC([C@H](CS[As](C)C)NC(CC[C@H](N)C(O)=O)=O)=O)=O | ||
| 分子式 | C12H22AsN3O6S | 分子量 | 411.3 |
| 溶解度 | 0.1mg/mL in ethanol and DMF, 10mg/mL in DMSO | 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 | 2.4313 mL | 12.1566 mL | 24.3132 mL |
| 5 mM | 0.4863 mL | 2.4313 mL | 4.8626 mL |
| 10 mM | 0.2431 mL | 1.2157 mL | 2.4313 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。
Darinaparsin: First Approval
Drugs 2022 Nov;82(16):1603-1609.PMID:36331780DOI:10.1007/s40265-022-01795-z.
Darinaparsin (Darvias®), an organoarsenic drug, is a novel mitochondrial-targeted anticancer agent currently being developed by Solasia Pharma K.K for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). An intravenous formulation of Darinaparsin has been approved for the treatment of relapsed or refractory PTCL in Japan, and preparation for the next stage of the clinical development program for this indication is currently underway in China, the USA and the EU. This article summarizes the milestones in the development of Darinaparsin leading to this first approval for relapsed or refractory PTCL.
Darinaparsin: a novel organic arsenical with promising anticancer activity
Expert Opin Investig Drugs 2009 Nov;18(11):1727-34.PMID:19780704DOI:10.1517/13543780903282759.
Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and is being investigated for antitumor properties in vitro and in vivo. While other arsenicals, including arsenic trioxide, have been used clinically, none have shown significant activity in malignancies outside of acute promyelocytic leukemia. Darinaparsin has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models. Here, we review the literature describing the signaling pathways and mechanisms of action of Darinaparsin and compare them to mechanisms of cell death induced by arsenic trioxide. Darinaparsin has overlapping, but distinct, signaling mechanisms. We also review the current results of clinical trials with Darinaparsin (both intravenous and oral formulations) that demonstrate significant antitumor activity.
Phase I studies of Darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: a pooled analysis of two phase I studies conducted in Japan and Korea
Jpn J Clin Oncol 2021 Feb 8;51(2):218-227.PMID:33051668DOI:10.1093/jjco/hyaa177.
Objective: Two phase I studies of Darinaparsin including Japanese and Korean patients with relapsed/refractory peripheral T-cell lymphoma were performed to evaluate its safety (primary purpose), efficacy and pharmacokinetic profile (ClinicalTrials.gov: NCT01435863 and NCT01689220). Methods: Patients received intravenous Darinaparsin for 5 consecutive days at 200 mg/m2/day in 4-week cycles, 300 mg/m2/day in 4-week cycles or 300 mg/m2/day in 3-week cycles. Results: Seventeen Japanese and 6 Korean patients were enrolled and treated. Drug-related adverse events developed in 18 patients (78%). Dose-limiting toxicity, grade 3 hepatic dysfunction, was reported on Day 15 of cycle 1 in 1 Japanese patient who received 300 mg/m2/day. The most common drug-related, grade ≥ 3 adverse events were lymphopenia (9%), neutropenia (9%) and thrombocytopenia (9%). No deaths occurred. In 14 evaluable patients, 1 and 3 patients had complete response and partial response, respectively. The plasma concentration-time profiles of arsenic, a surrogate marker for Darinaparsin, were similar between Japanese and Korean patients. No significant difference was found in its pharmacokinetic profile. Conclusions: These data indicate the good tolerability and potential efficacy of Darinaparsin in patients with relapsed/refractory peripheral T-cell lymphoma. Darinaparsin 300 mg/m2/day for 5 consecutive days in 3-week cycles is the recommended regimen for phase II study.
Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer
Clin Cancer Res 2012 Jun 15;18(12):3366-76.PMID:22535156DOI:10.1158/1078-0432.CCR-11-3179.
Purpose: Hypoxia is an important characteristic of the solid tumor microenvironment and constitutes a barrier for effective radiotherapy. Here, we studied the effects of Darinaparsin (an arsenic cytotoxin) on survival and radiosensitivity of tumor cells in vitro under normoxia and hypoxia and in vivo using xenograft models, compared to effects on normal tissues. Experimental design: The cytotoxicity and radiosensitization of Darinaparsin were first tested in vitro in a variety of solid tumor cell lines under both normoxia and hypoxia and compared with arsenic trioxide (ATO, an arsenical with reported cytotoxic and radiosensitizing activities on tumor cells). The effects were then tested in mouse models of xenograft tumors derived from tumor cell lines and clinical tumor specimens. The potential mechanisms of Darinaparsin effects, including reactive oxygen species (ROS) generation, cellular damage, and changes in global gene expression, were also investigated. Results: In comparison with ATO, Darinaparsin had significantly higher in vitro cytotoxic and radiosensitizing activities against solid tumor cells under both normoxia and hypoxia. In vivo experiments confirmed these activities at doses that had no systemic toxicities. Importantly, Darinaparsin did not radiosensitize normal bone marrow and actually radioprotected normal intestinal crypts. The darinaparsin-mediated antitumor effects under hypoxia were not dependent on ROS generation and oxidative damage, but were associated with inhibition of oncogene (RAS and MYC)-dependent gene expression. Conclusion: Darinaparsin has significant and preferential cytotoxic and radiosensitizing effects on solid tumors as compared with normal cells. Darinaparsin may therefore increase the therapeutic index of radiation therapy and has near term translational potential.
Darinaparsin is a multivalent chemotherapeutic which induces incomplete stress response with disruption of microtubules and Shh signaling
PLoS One 2011;6(11):e27699.PMID:22110729DOI:10.1371/journal.pone.0027699.
Chemotherapeutics and other pharmaceuticals are common sources of cellular stress. Darinaparsin (ZIO-101) is a novel organic arsenical under evaluation as a cancer chemotherapeutic, but the drug's precise mechanism of action is unclear. Stress granule formation is an important cellular stress response, but the mechanisms of formation, maintenance, and dispersal of RNA-containing granules are not fully understood. During stress, small, diffuse granules initially form throughout the cytoplasm. These granules then coalesce near the nucleus into larger granules that disperse once the cellular stress is removed. Complete stress granule formation is dependent upon microtubules. Human cervical cancer (HeLa) cells, pre-treated with nocodazole for microtubule depolymerization, formed only small, diffuse stress granules upon sodium arsenite treatment. Darinaparsin, as a single agent, also induced the formation of small, diffuse stress granules, an effect similar to that of the combination of nocodazole with sodium arsenite. Darinaparsin inhibited the polymerization of microtubules both in vivo and in vitro. Interestingly, upon removal of Darinaparsin, the small, diffuse stress granules completed formation with coalescence in the perinuclear region prior to disassembly. These results indicate that RNA stress granules must complete formation prior to disassembly, and completion of stress granule formation is dependent upon microtubules. Finally, treatment of cells with Darinaparsin led to a reduction in Sonic hedgehog (Shh) stimulated activation of Gli1 and a loss of primary cilia. Therefore, Darinaparsin represents a unique multivalent chemotherapeutic acting on stress induction, microtubule polymerization, and Shh signaling.