Darinaparsin
(Synonyms: Dimethylarsinic glutathione) 目录号 : GC43379Darinaparsin是一种新型有机砷化合物，对HL-60、Jurkat及HepG2、A549的IC₅₀为0.5–3.0µM，目前用于复发/难治性淋巴瘤及实体瘤的临床前与临床研究。
Cas No.:69819-86-9
Sample solution is provided at 25 µL, 10mM.
Darinaparsin is a novel organic arsenic compound with IC₅₀ values of 0.5–3.0µM against HL-60, Jurkat, HepG2, and A549 cells[1]. Darinaparsin is currently under preclinical and clinical investigation for relapsed/refractory lymphomas and solid tumors[2]. Darinaparsin accumulates in mitochondria, induces mitochondrial membrane depolarization, and triggers reactive oxygen species (ROS) bursts, thereby activating intrinsic apoptosis pathways[4]. Additionally, Darinaparsin downregulates pro-angiogenic factors such as VEGF and IL-8, inhibiting endothelial tube formation [4].
In vitro, treatment of human multiple myeloma cells (8226/S, KMS11) with 2µM Darinaparsin for 6–24 hours significantly upregulated BH3-only proteins like Noxa and Bim, activating the mitochondrial apoptosis pathway. In arsenic trioxide (ATO)-resistant cell lines (8226/S-ATOR05), Darinaparsin still induced apoptosis in a dose-dependent manner, with higher uptake efficiency than ATO in parental cells[5]. Pre-treatment of prostate (HI-LAPC-4), pancreatic (PANC-1), and other solid tumor cells with 3µmol/L Darinaparsin for 4 hours, followed by γ-irradiation under normoxia or hypoxia, significantly enhanced radiosensitivity and induced apoptosis in tumor cells, without sensitizing normal bone marrow and protecting intestinal crypt cells from radiation damage[6].
In vivo, Darinaparsin (100mg/kg) administered via intraperitoneal injection every other day for 10 days in nude mice bearing Du145 or PC3 xenografts significantly inhibited tumor growth without causing weight loss or other toxic effects[7]. Combined treatment with Darinaparsin (50mg/kg) and BMN673 (330mg/kg) via intraperitoneal injection every other day for 14 days in nude mice with DMS273 small-cell lung cancer xenografts also significantly inhibited tumor growth without causing weight loss or other toxic effects[8].
References:
[1] Mann KK, Wallner B, Lossos IS, et al. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin Investig Drugs. 2009 Nov;18(11):1727-34.
[2] Frampton JE. Darinaparsin: First Approval. Drugs. 2022 Nov;82(16):1603-1609.
[3] Yuan B, Kikuchi H, Li J, et al. Cytotoxic Effects of Darinaparsin, a Novel Organic Arsenical, against Human Leukemia Cells. Int J Mol Sci. 2023 Jan 23;24(3):2282.
[4] Nielsen TH, Johnson N, Garnier N, et al. Monitoring Response and Resistance to the Novel Arsenical Darinaparsin in an AML Patient. Front Pharmacol. 2013 Feb 12;4:9.
[5] Matulis SM, Morales AA, Yehiayan L, et al. Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line. Mol Cancer Ther. 2009 May;8(5):1197-206.
[6] Tian J, Zhao H, Nolley R, et al. Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer. Clin Cancer Res. 2012 Jun 15;18(12):3366-76.
[7] Bansal N, Farley NJ, Wu L, et al. Darinaparsin inhibits prostate tumor-initiating cells and Du145 xenografts and is an inhibitor of hedgehog signaling. Mol Cancer Ther. 2015 Jan;14(1):23-30.
[8] Cao GZ, Ma LY, Zhang ZH, et al. Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors. Acta Pharmacol Sin. 2023 Apr;44(4):841-852.
Darinaparsin是一种新型有机砷化合物，对HL-60、Jurkat及HepG2、A549的IC₅₀为0.5–3.0µM[1]，目前用于复发/难治性淋巴瘤及实体瘤的临床前与临床研究[2]。研究发现，Darinaparsin过在线粒体内蓄积、诱导线粒体膜电位下降及活性氧（ROS）爆发，激活内源性凋亡通路[3]。此外，Darinaparsin还可下调NF-κB、IL-8等细胞因子，抑制炎症反应[4]。
在体外，Darinaparsin（2μM）处理人多发性骨髓瘤细胞（8226/S、KMS11）6–24h，可显著诱导Noxa、Bim等BH3-only蛋白上调并激活线粒体凋亡通路；在三氧化二砷（ATO）耐药株（8226/S-ATOR05）中，Darinaparsin仍能剂量依赖性诱导细胞凋亡，而对亲代株的摄取效率高于ATO[5]。Darinaparsin（3μmol/L）预处理前列腺（HI-LAPC-4）、胰腺（PANC-1）等多种实体瘤细胞4h，随后在常氧或缺氧条件下给予γ-射线照射，Darinaparsin显著增强肿瘤细胞放射敏感性并诱导凋亡，但对正常骨髓无放射增敏作用，且可保护肠道隐窝细胞免受辐射损伤[6]。
在体内，Darinaparsin（100mg/kg）隔日腹腔注射，用于处理携带Du145或PC3荷瘤的裸鼠，连续10天；结果显示，Darinaparsin显著抑制肿瘤生长，且未引起体重下降或其他毒性反应[7]。Darinaparsin（50mg/kg）联合BMN673（330mg/kg）隔日腹腔注射，用于处理携带DMS273小细胞肺癌异种移植瘤的裸鼠，持续14天；联合治疗显著抑制肿瘤生长，且未引起体重下降或其他毒性反应[8]。
| Cell experiment [1]: | |
Cell lines | Human prostate cancer cells (HI-LAPC-4, PC-3, PANC-1, HeLa, SNB-75) |
Preparation Method | Cells were seeded in 6-well plates or 96-well plates, grown to 70–80% confluence, and incubated overnight in hypoxia chambers (0.5% O₂) before treatment. Cells were divided into four groups: control (normoxia), Darinaparsin alone: 3μmol/L Darinaparsin for 4h under normoxia or hypoxia, radiation alone, and Darinaparsin (3μmol/L Darinaparsin for 4h under normoxia or hypoxia) + radiation. |
Reaction Conditions | 3μmol/L; 4h |
Applications | Darinaparsin significantly decreased tumor-cell viability and clonogenic survival under both normoxia and hypoxia, induced G₂/M arrest and apoptosis. |
| Animal experiment [2]: | |
Animal models | Nude rats bearing Du145 xenografts |
Preparation Method | Once tumors reached ~100mm³, rats were randomized and treated with Darinaparsin (100mg/kg; i.p. every other day for 10 days) or vehicle (saline). Tumor volume and body weight were monitored thrice weekly; tumors and blood were harvested on day 45 for histology and pharmacokinetic analyses. |
Dosage form | 100mg/kg; i.p. |
Applications | Darinaparsin significantly inhibited tumor-initiating-cell–driven xenograft growth, reduced tumor volume by >50 % versus controls, and showed no systemic toxicity (no weight loss or organ damage). |
References: | |
| 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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| 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 |
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| 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 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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