Darinaparsin | ZIO-101 | CAS#69819-86-9

MedKoo Cat#: 200850 | Name: Darinaparsin

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Darinaparsin, also know as ZIO-101 and SP-02, is a small-molecule organic arsenical with potential antineoplastic activity. Although the exact mechanism of action is unclear, darinaparsin, a highly toxic metabolic intermediate of inorganic arsenicals (iAs) that occurs in vivo, appears to generate volatile cytotoxic arsenic compounds when glutathione (GSH) concentrations are low. The arsenic compounds generated from darinaparsin disrupt mitochondrial bioenergetics, producing reactive oxygen species (ROS) and inducing ROS-mediated tumor cell apoptosis; in addition, this agent or its byproducts may initiate cell death by interrupting the G2/M phase of the cell cycle and may exhibit antiangiogenic effects.

Chemical Structure

Darinaparsin

CAS#69819-86-9

Theoretical Analysis

MedKoo Cat#: 200850

Name: Darinaparsin

CAS#: 69819-86-9

Chemical Formula: C12H22AsN3O6S

Exact Mass: 411.0445

Molecular Weight: 411.31

Elemental Analysis: C, 35.04; H, 5.39; As, 18.22; N, 10.22; O, 23.34; S, 7.80

Price and Availability

Size	Price	Availability
5mg	USD 90.00	Ready to ship
10mg	USD 150.00	Ready to ship
25mg	USD 250.00	Ready to ship
50mg	USD 450.00	Ready to ship
100mg	USD 750.00	Ready to ship
200mg	USD 1,250.00	Ready to ship
500mg	USD 2,450.00	Ready to ship
1g	USD 3,850.00	Ready to ship

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Related CAS #

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Synonym

ZIO 101; ZIO101; ZIO-101; SP-02; SP 02; SP02; Darinaparsin; Zinapar.

IUPAC/Chemical Name

(S)-2-amino-5-(((R)-1-((carboxymethyl)amino)-3-((dimethylarsino)thio)-1-oxopropan-2-yl)amino)-5-oxopentanoic acid

InChi Key

JGDXFQORBMPJGR-YUMQZZPRSA-N

InChi Code

InChI=1S/C12H22AsN3O6S/c1-13(2)23-6-8(11(20)15-5-10(18)19)16-9(17)4-3-7(14)12(21)22/h7-8H,3-6,14H2,1-2H3,(H,15,20)(H,16,17)(H,18,19)(H,21,22)/t7-,8-/m0/s1

SMILES Code

O=C(O)[C@@H](N)CCC(N[C@@H](CS[As](C)C)C(NCC(O)=O)=O)=O

Appearance

White to off-white solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in water

Shelf Life

>2 years if stored properly

Drug Formulation

This drug may be formulated in water

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot#YXM61017

QC Data

View QC data: current batch, Lot#YMX61017

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Darinaparsin is a dimethylated arsenic linked to glutathione, and 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)

In vitro activity:

The purpose of this experiment was to investigate the potency of darinaparsin in TCL and HL cells lines Darinaparsin (1–3µM) treatment resulted in accumulation of cells predominantly at G2 cell cycle in both Jurkat and L428 cell lines (Figure 2A). In Jurkat, treatment with 1µM or 3µM resulted in accumulation of cells at G2 with 26% and 13% respectively, compared with presence of 11% G2 cells in the untreated control (Figure 2A). The decline in G2 with increased darinaparsin concentrations is likely due to decreased cell viability and associated increased apoptosis at higher dosing. In L428, treatment with 1µM or 3µM darinaparsin resulted in a significant accumulation of 29% (p<0.001) and 74% (p<0.0001) cells respectively at G2, compared with 10% in untreated control. Notably, treatment with 1 or 3 µM darinaparsin in L428 (HL) resulted only in a moderate effect on cell viability compared with other HL cell lines (Figure 1B). Therefore, these results suggest that perhaps cell cycle arrest with darinaparsin in L428 may impact the cytotoxic response in this cell line. Reference: Clin Cancer Res. 2014 Dec 1; 20(23): 6023–6033. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281835/

In vivo activity:

The in vivo efficacy of darinaparsin was investigated using tumor xenografts derived using either Jurkat (TCL) or L540 (HL) cell lines. Results from Jurkat-derived xenograft experiments showed with darinaparsin administration a significant 3.6- and 4.3-fold reduction in the average approximate size of the tumor with 40 mg/kg (average tumor size, 532mm3) and 70 mg/kg (average tumor size, 447mm3), respectively, compared with the average size of tumor (1929mm3) in the vehicle treated control group (p<0.0001, two way repeated ANOVA) (Figure 3A). There was significantly improved survival by Kaplan Meier in Jurkat SCID mice treated with darinaparsin compared with control (p<0.0001) (Figure 3B). While the extent of tumor growth inhibition was similar with 40 or 70mg/kg of darinaparsin, there was no appreciable change in total body weight in the treatment with 40mg/kg dose darinaparsin; however increased dosing to 70mg/kg initially resulted in a 10% loss of total body weight by 5 days and subsequently returned to normal once treatment was completed (Figure 3C). L540-derived SCID xenograft mice initially received 100 mg/kg darinaparsin for 5 days, and based on clinical observations, the dosage subsequently adjusted to 70 mg/kg for days 9, 10 and 11. Treatment with darinaparsin in L540 xenograft SCID mice resulted in a 3.2-fold reduction in the average size of the tumor (tumor size, 619 mm3) compared with control (2003 mm3) at four weeks (p=<0.001, two way repeated measurement ANOVA, GraphPad Prism 5) (Figure 3D). Kaplan Meier survival analysis showed a significant increase in survival with darinaparsin treatment compared with control groups (p< 0.0001, log rank, Sigma Pad Prism5) (Figure 3E). Treatment with 70mg/kg initially resulted in 10% loss of total body weight by day 5 and the observed body weight returned to normal once the treatment was completed (Figure 3F) in a similar manner as observed with Jurkat-derived xenograft tumors. Reference: Clin Cancer Res. 2014 Dec 1; 20(23): 6023–6033. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4281835/

	Solvent	mg/mL	mM
Solubility
	DMSO	10.0	24.31

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 411.31 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Tian J, Zhao H, Nolley R, Reese SW, Young SR, Li X, Peehl DM, Knox SJ. Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer. Clin Cancer Res. 2012 Jun 15;18(12):3366-76. doi: 10.1158/1078-0432.CCR-11-3179. Epub 2012 Apr 25. PMID: 22535156; PMCID: PMC5518752. 2. Ravi D, Bhalla S, Gartenhaus RB, Crombie J, Kandela I, Sharma J, Mazar A, Evens AM. 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. 2014 Dec 1;20(23):6023-33. doi: 10.1158/1078-0432.CCR-14-1532. Epub 2014 Oct 14. PMID: 25316819; PMCID: PMC4281835.

In vitro protocol:

In vivo protocol:

1: Frampton JE. Darinaparsin: First Approval. Drugs. 2022 Nov;82(16):1603-1609. doi: 10.1007/s40265-022-01795-z. Erratum in: Drugs. 2022 Nov 14;: PMID: 36331780. 2: Kim WS, Fukuhara N, Yoon DH, Yamamoto K, Uchida T, Negoro E, Izutsu K, Terui Y, Nakajima H, Ando K, Suehiro Y, Kang HJ, Ko PS, Nagahama F, Sonehara Y, Nagai H, Tien HF, Kwong YL, Tobinai K. Darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma: results of an Asian phase 2 study. Blood Adv. 2023 Sep 12;7(17):4903-4912. doi: 10.1182/bloodadvances.2022008615. PMID: 36661315; PMCID: PMC10463191. 3: Mann KK, Wallner B, Lossos IS, Miller WH Jr. Darinaparsin: a novel organic arsenical with promising anticancer activity. Expert Opin Investig Drugs. 2009 Nov;18(11):1727-34. doi: 10.1517/13543780903282759. PMID: 19780704. 4: Frampton JE. Correction to: Darinaparsin: First Approval. Drugs. 2022 Nov;82(16):1611. doi: 10.1007/s40265-022-01807-y. Erratum for: Drugs. 2022 Nov;82(16):1603-1609. PMID: 36376781. 5: Tian J, Zhao H, Nolley R, Reese SW, Young SR, Li X, Peehl DM, Knox SJ. Darinaparsin: solid tumor hypoxic cytotoxin and radiosensitizer. Clin Cancer Res. 2012 Jun 15;18(12):3366-76. doi: 10.1158/1078-0432.CCR-11-3179. Epub 2012 Apr 25. PMID: 22535156; PMCID: PMC5518752. 6: Cao GZ, Ma LY, Zhang ZH, Wang XL, Hua JH, Zhang JH, Lv Y, Zhang SB, Ou J, Lin WC. Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors. Acta Pharmacol Sin. 2023 Apr;44(4):841-852. doi: 10.1038/s41401-022-00994-4. Epub 2022 Oct 17. Erratum in: Acta Pharmacol Sin. 2022 Nov 13;: PMID: 36253561; PMCID: PMC10042828. 7: Yuan B, Kikuchi H, Li J, Kawabata A, Yao K, Takagi N, Okazaki M. Cytotoxic Effects of Darinaparsin, a Novel Organic Arsenical, against Human Leukemia Cells. Int J Mol Sci. 2023 Jan 23;24(3):2282. doi: 10.3390/ijms24032282. PMID: 36768603; PMCID: PMC9916914. 8: Matulis SM, Morales AA, Yehiayan L, Croutch C, Gutman D, Cai Y, Lee KP, Boise LH. 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. doi: 10.1158/1535-7163.MCT-08-1072. Epub 2009 May 5. PMID: 19417148; PMCID: PMC2891844. 9: Ogura M, Kim WS, Uchida T, Uike N, Suehiro Y, Ishizawa K, Nagai H, Nagahama F, Sonehara Y, Tobinai K. 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. doi: 10.1093/jjco/hyaa177. PMID: 33051668; PMCID: PMC7869082. 10: Mason TA, Kolobova E, Liu J, Roland JT, Chiang C, Goldenring JR. Darinaparsin is a multivalent chemotherapeutic which induces incomplete stress response with disruption of microtubules and Shh signaling. PLoS One. 2011;6(11):e27699. doi: 10.1371/journal.pone.0027699. Epub 2011 Nov 15. PMID: 22110729; PMCID: PMC3216988. 11: Bansal N, Farley NJ, Wu L, Lewis J, Youssoufian H, Bertino JR. 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. doi: 10.1158/1535-7163.MCT-13-1040. Epub 2014 Nov 7. PMID: 25381261. 12: Cao GZ, Ma LY, Zhang ZH, Wang XL, Hua JH, Zhang JH, Lv Y, Zhang SB, Ou J, Lin WC. Author Correction: Darinaparsin (ZIO-101) enhances the sensitivity of small-cell lung cancer to PARP inhibitors. Acta Pharmacol Sin. 2023 May;44(5):1105-1106. doi: 10.1038/s41401-022-01019-w. Erratum for: Acta Pharmacol Sin. 2023 Apr;44(4):841-852. PMID: 36372854; PMCID: PMC10104812. 13: Xu X, Wang H, Li H, Hu X, Zhang Y, Guan X, Toy PH, Sun H. S-Dimethylarsino- glutathione (darinaparsin®) targets histone H3.3, leading to TRAIL-induced apoptosis in leukemia cells. Chem Commun (Camb). 2019 Oct 29;55(87):13120-13123. doi: 10.1039/c9cc07605k. PMID: 31616884. 14: Nielsen TH, Johnson N, Garnier N, Kwan S, Yao L, Cocolakis E, Hébert J, Morgan RA, Paquet E, Callahan KP, Jordan CT, Assouline S, Miller WH Jr, Mann KK. Monitoring Response and Resistance to the Novel Arsenical Darinaparsin in an AML Patient. Front Pharmacol. 2013 Feb 12;4:9. doi: 10.3389/fphar.2013.00009. PMID: 23408639; PMCID: PMC3570070. 15: Ravi D, Bhalla S, Gartenhaus RB, Crombie J, Kandela I, Sharma J, Mazar A, Evens AM. 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. 2014 Dec 1;20(23):6023-33. doi: 10.1158/1078-0432.CCR-14-1532. Epub 2014 Oct 14. PMID: 25316819; PMCID: PMC4281835. 16: Garnier N, Redstone GG, Dahabieh MS, Nichol JN, del Rincon SV, Gu Y, Bohle DS, Sun Y, Conklin DS, Mann KK, Miller WH Jr. The novel arsenical darinaparsin is transported by cystine importing systems. Mol Pharmacol. 2014 Apr;85(4):576-85. doi: 10.1124/mol.113.089433. Epub 2014 Jan 15. PMID: 24431147. 17: Yao K, Sonehara Y, Nagahama F. [Pharmacological profile and clinical study results of darinaparsin (DARVIAS® injection 135 ‍mg), an organic arsenic product, for relapsed or refractory peripheral t-cell lymphoma]. Nihon Yakurigaku Zasshi. 2023;158(5):408-418. Japanese. doi: 10.1254/fpj.23047. PMID: 37673618. 18: Wu J, Henderson C, Feun L, Van Veldhuizen P, Gold P, Zheng H, Ryan T, Blaszkowsky LS, Chen H, Costa M, Rosenzweig B, Nierodzik M, Hochster H, Muggia F, Abbadessa G, Lewis J, Zhu AX. Phase II study of darinaparsin in patients with advanced hepatocellular carcinoma. Invest New Drugs. 2010 Oct;28(5):670-6. doi: 10.1007/s10637-009-9286-9. Epub 2009 Jun 30. PMID: 19565187. 19: Chowdhury T, Roymahapatra G, Mandal SM. In Silico Identification of a Potent Arsenic Based Approved Drug Darinaparsin against SARS-CoV-2: Inhibitor of RNA Dependent RNA polymerase (RdRp) and Essential Proteases. Infect Disord Drug Targets. 2021;21(4):608-618. doi: 10.2174/1871526520666200727153643. PMID: 32718300. 20: Negoro E, Yamauchi T, Fukuhara N, Yamamoto K, Uchida T, Izutsu K, Maruyama D, Terui Y, Nakajima H, Ando K, Suehiro Y, Choi I, Kanemura N, Nakamura N, Yamamoto G, Maeda Y, Shibayama H, Nagahama F, Sonehara Y, Nagai H, Tien HF, Kwong YL, Kim WS, Tobinai K. Japanese subgroup analysis in the Asian phase II study of darinaparsin in patients with relapsed or refractory peripheral T-cell lymphoma. J Clin Exp Hematop. 2023;63(2):108-120. doi: 10.3960/jslrt.23005. PMID: 37380467; PMCID: PMC10410617.