Darinaparsin
ダリナパルシン , Darvias
JAPAN 2022 APPROVED, PMDA 2022/6/20
(2S)-2-amino-5-[[(2R)-1-(carboxymethylamino)-3-dimethylarsanylsulfanyl-1-oxopropan-2-yl]amino]-5-oxopentanoic acid
Glycine, L-gamma-glutaMyl-S-(diMethylarsino)-L-cysteinyl-
| Formula | C12H22AsN3O6S |
|---|---|
| CAS | 69819-86-9 |
| Mol weight | 411.3062 |
| Efficacy | Antineoplastic |
|---|---|
| Comment | organic arsenical |
Zinapar, ZIO-101, DMAs(III)G, clarinaparsin, UNII-9XX54M675G, SP-02L
- OriginatorTexas A&M University; University of Texas M. D. Anderson Cancer Center
- DeveloperSolasia Pharma; ZIOPHARM Oncology
- ClassAmines; Antineoplastics; Arsenicals; Oligopeptides; Pentanoic acids; Small molecules; Sulfides
- Mechanism of ActionApoptosis stimulants; Cell cycle inhibitors; Reactive oxygen species stimulants
- Orphan Drug StatusYes – Peripheral T-cell lymphoma
- PreregistrationPeripheral T-cell lymphoma
- DiscontinuedLiver cancer; Lymphoma; Multiple myeloma; Non-Hodgkin’s lymphoma; Solid tumours
- 28 Mar 2022No recent reports of development identified for phase-I development in Peripheral-T-cell-lymphoma in China (IV, Injection)
- 26 Jan 2022ZIOPHARM Oncology is now called Alaunos Therapeutics
- 11 Dec 2021Safety and efficacy data from a phase II trial in Peripheral T-cell lymphoma presented at the 63rd American Society of Hematology Annual Meeting and Exposition (ASH-2021)
Darinaparsin 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. Compared to inorganic arsenic compounds such as arsenic trioxide (As2O3), darinaparsin appears to exhibit a wide therapeutic window.
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.
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.
PAPER
Biochemical Pharmacology (Amsterdam, Netherlands), 126, 79-86; 2017
PATENT
WO 2015085208
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015085208
Preparation of Darinaparsin
[0071] Sterile water (15.5 L) and ethyl alcohol (200 proof, 15.5 L) were charged in a reaction flask prior to the addition of L-glutathione (3.10 kg). While being stirred, the reaction mixture was cooled to 0-5 °C prior to the addition of triethylamine (1.71 L). Stirring was continued until most of the solids were dissolved and the solution was filtered. After filtration, the reaction mixture was cooled to 0-5 °C prior to the addition of chlorodimethylarsine (1.89 kg) over 115 minutes while maintaining the temperature at 0-5 °C. Stirring continued at 0-5 °C for 4 hours before acetone (30.6 L) was added over 54 minutes while maintaining the temperature at 0-5 °C. The suspension was stored at 0-5°C overnight prior to filtration. The solid was collected in a filter funnel, washed successively with ethyl alcohol (200 proof, 13.5 L) and acetone (13.5 L) and dried in suction for 23 minutes. A second similar run was performed and the collected solids from both runs were combined. Ethyl alcohol (200 proof, 124 L) and the combined solids (11.08 kg) were charged in a vessel. The slurry was stirred at ambient temperature for 2 hours before filtration, washing successively with ethyl alcohol (200 proof, 27 L) and acetone (27 L) and dried in suction for 60 minutes. The resulting solid was transferred to drying trays and dried in a vacuum oven at ambient temperature for 66 hours to provide darinaparsin as a solid with the differential scanning calorimetry (DSC) thermogram of Figure 1, with an extrapolated onset temperature at about 191.36° C and a peak temperature at about 195.65° C.
PATENT
WO 2010021928
Step 1
Dimethylchloroarsine. Dimethylarsinic acid, (CH3)2As(O)OH was supplied by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was accompanied by a statement of its purity and was supplied as 99.7% pure. The dimethylarsinic acid was dissolved in water-hydrochloric acid to pH 3. A stream of sulfur dioxide was passed through this solution for about one hour. Dimethylchloroarsine separated as a heavy, colorless oil. The two liquid phases, water/(CH3)2AsCl were separated using a separatory funnel. The chlorodimethylarsine was extracted into diethylether and the ether solution was dried over anhydrous sodium sulfate. The dried solution was transferred to a distillation flask which was heated slowly to evaporate the ether. The remaining liquid, dimethylchloroarsine was purified by distillation. The fraction boiling at 106-109°C was collected. The product, a colorless oil. 1H NMR resonance at 1.65 ppm.
Step 2
SGLU-1: Glutathione (14.0 g, 45.6 mmol) was stirred rapidly in glyme while dimethylchoroarsine (6.5 g, 45.6 mmol) was added dropwise. Pyridine (6.9 g, 91.2 mmol) was then added to the slurry and the mixture was subsequently heated to reflux. The heat was removed immediately and the mixture stirred at room temperature for 4 h. Isolation of the resultant insoluble solid and recrystallization from ethanol afforded 4 as the pyridine hydrochloride complex (75% yield). mp 115-118°C; NMR (D20) δ1.35 (s, 6H), 1.9-4.1 (m’s, 10H), 7.8-9.0 (m, 5H); mass spectrum (m/e) 140, 125, 110, 105, 79, 52, 45, 36.
PATENT
WO 2009075870
Step 1
Example 1. Preparation of Dimethylchloroarsine (DMCA). A 3-neck round-bottom flask (500 mL) equipped with mechanical stirrer, inlet for nitrogen, thermometer, and an ice bath was charged with cacodylic acid (33 g, 0.23 mol) and cone. hydrochloric acid (67 mL). In a separate flask, a solution of SnCl2·2H2O (54 g, 0.239 mol) in cone. hydrochloric acid (10 mL) was prepared. The SnCl2·2 H2O solution was added to the cacodylic acid in HCl solution under nitrogen while maintaining the temperature between 5 °C and 10 °C. After the addition was complete, the ice bath was removed and the reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was transferred to a separatory funnel and the upper layer (organic) collected. The bottom layer was extracted with dichloromethane (DCM) (2 × 25 mL). The combined organic extract was washed with 1 N HCl (2 × 10 mL) and water (2 × 20 mL). The organic extract was dried over MgSO4 and DCM was removed by rotary evaporation (bath temperature 80 °C, under nitrogen, atmospheric pressure). The residue was further distilled under nitrogen. Two tractions of DMCA were collected. The first fraction contained some DCM and the second fraction was of suitable quality (8.5 g, 26% yield). The GC analysis confirmed the identity and purity of the product.
Step 2
Example 3. Preparation of S-Dimethylarsinoglutathione (SGLU-1). In a 3 L three-neck flask equipped with a mechanic stirrer, dropping funnel and thermometer under an inert atmosphere was prepared a suspension of glutathione (114.5 g, 0.37 mol) in a 1:1 (v/v) mixture of water/ethanol (1140 mL) and cooled to below 5 °C. The mixture was treated slowly (over 15 min) with triethylamine (63.6 mL, 0.46 mol) while maintaining the temperature below 20 °C. The mixture was cooled to 4 °C and stirred for 15 min and then the traces of undissolved material removed by filtration. The filtrate was transferred in a clean 3 L three-neck flask equipped with a mechanic stirrer, dropping funnel, nitrogen inlet, and thermometer and DMCA (70 g, 0.49 mol) (lot # 543-07-01-44) was added slowly while maintaining the temperature at 3-4°C. The reaction mixture was stirred at 1-4°C for 4 h, and acetone (1.2 L) was added over a period of 1 h. The mixture was stirred for 90 min between 2 and 3°C and the resulting solid was isolated by filtration. The product was washed with ethanol (2 × 250 mL) and acetone (2 × 250 mL) and the wet solids were suspended in ethanol 200 Proof (2000 mL). The product was isolated by filtration, washed with ethanol (2 × 250 mL) and acetone (2 × 250 mL) and dried in vacuum for 2 days at RT to give 115 g (75%) of SGLU-1, HPLC purity > 99.5% (in process testing).
PATENT
WO 2007027344
Example 2 Preparation of S-Dimethylarsinoglutathione A 5 L, three necked round bottom flask was equipped with a mechanical stirrer assembly, thermometer, addition funnel, nitrogen inlet, and a drying tube was placed in a cooling bath. A polyethylene crock was charged with glutathione-reduced (200 g) and deionized water (2 L) and stirred under a nitrogen atmosphere to dissolve all solids. The mixture was filtered to remove any insoluble material and the filtrate was transferred to the 5 L flask. While stirring, ethanol, 200 proof (2 L) was added and the clear solution was cooled to 0-5° C. using an ice/methanol bath. Pyridine (120 g) was added followed by a dropwise addition of Me2AsCl (120 g) over a minimum of 1 hour. The reaction mixture was stirred at 0-5° C. for a minimum of 2 hours prior to removal of the cooling bath and allowing the mixture to warm to room temperature under a nitrogen atmosphere with stirring. The reaction mixture was stirred overnight (>15 hrs) at room temperature under a nitrogen atmosphere at which time a white solid may precipitate. The reaction mixture was concentrated to a slurry (liquid and solid) at 35-45° C. using oil pump vacuum to provide a white solid residue. As much water as possible is removed, followed by two coevaporations with ethanol to azeotrope the last traces of water. The white solid residue was slurried in ethanol, 200 pf. (5 L) under a nitrogen atmosphere at room temperature overnight. The white solid was filtered and washed with ethanol, 200 pf. (2×500 mL) followed by acetone, ACS (2×500 mL). The resulting solid was transferred to drying trays and vacuum oven dried overnight at 25-35° C. using oil pump vacuum to provide pyridinium hydrochloride-free S-dimethylarsinoglutathione as a white solid. melting point of 189-190° C.
PATENT
WO 20060128682
Step 1
Dimethylchloroarsine. Dimethylarsinic acid, (CH3)2As(O)OH was supplied by the Luxembourg Chemical Co., Tel Aviv, Israel. The product was accompanied by a statement of its purity and was supplied as 99.7% pure. The dimethylarsinic acid was dissolved in water-hydrochloric acid to pH 3. A stream of sulfur dioxide was passed through this solution for about one hour. Dimethylchloroarsine separated as a heavy, colorless oil. The two liquid phases, water/(CH3)2AsCl were separated using a separatory funnel. The chlorodimethylarsine was extracted into diethylether and the ether solution was dried over anhydrous sodium sulfate. The dried solution was transferred to a distillation flask which was heated slowly to evaporate the ether. The remaining liquid, dimethylchloroarsine was purified by distillation. The fraction boiling at 106-109° C. was collected. The product, a colorless oil. 1H NMR resonance at 1.65 ppm.
Step 2
Pyridine Hydrochloride Free Synthesis of S-Dimethylarsinoglutathione (GLU) Dimethylarsinoglutathione is made using an adapted of Chen (Chen, G. C., et al. Carbohydrate Res. (1976) 50: 53-62) the contents of which are hereby incorporated by reference in their entirety. Briefly, dithiobis(dimethylarsinoglutamine) is dissolved in dichloromethane under nitrogen. Tetramethyldiarsine is added dropwise to the solution and the reaction is stirred overnight at room temperature under nitrogen and then exposed to air for 1 h. The mixture is then evaporated to dryness and the residue is washed with water and dried to give a crude solid that is recrystallized from methanol to give S-dimethylarsinoglutathione.
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Solasia Announces Submission of New Drug Application for Anti-cancer Drug DARINAPARSIN for Peripheral T-Cell Lymphoma in Japan
Solasia Pharma K.K. (TSE: 4597, Headquarters: Tokyo, Japan, President & CEO: Yoshihiro Arai, hereinafter “Solasia”) today announced submission of a New Drug Application (NDA) for its new anti-cancer drug darinaparsin (generic name, development code: SP-02) as a treatment for relapsed or refractory peripheral T-cell lymphoma to the Ministry of Health, Labour and Welfare (MHLW). Based on positive results of R&D on darinaparsin, centered primarily on the results of the Asian Multinational Phase 2 Study (study results released in June 2020), Solasia filed an NDA for the drug with the regulatory authority in Japan ahead of anywhere else in the world.
Solasia expects to obtain regulatory approval in 2022 and to also launch in the same year. If approved and launched, darinaparsin would be the third drug Solasia successfully developed and brought to market since its founding and is expected to contribute to the treatment of PTCL.
Mr. Yoshihiro Arai, President and CEO of Solasia, commented as follows:
“No standard treatment has been established for relapsed or refractory PTCL as of yet. I firmly believe that darinaparsin, with its novel mechanism of action that differs from those of already approved drugs, will contribute to patients and healthcare providers at clinical sites as a new treatment option for relapsed or refractory PTCL. Since founding, Solasia has conducted R&D on five pipeline drugs. Of the five, we have successfully developed and brought to market two drugs, i.e., began providing them to patients, and today, we submitted an NDA for our first anti-cancer drug. Under our mission to provide patients with ‘Better Medicine for a Brighter Tomorrow’, we will continue aiming to contribute to patients’ treatment and enhanced quality of life. ”
About darinaparsin (SP-02)
Darinaparsin, an organoarsenic compound with anticancer activity, is a novel mitochondrial-targeted agent being developed for the treatment of various hematologic and solid tumors. The proposed mechanism of action of the drug involves the disruption of mitochondrial function, increased production of reactive oxygen species, and modulation of intracellular signal transduction pathways. Darinaparsin is believed to exert anticancer effect by inducing cell cycle arrest and apoptosis. Darinaparsin has been granted orphan drug designation in the US and EU.
For more information, please visit at https://solasia.co.jp/en/pipeline/sp-02.html
About Asian Multinational Phase 2 Study
The Asian Multinational Phase 2 Study was a multinational, multicenter, single-arm, open-label, non-randomized study to evaluate the efficacy and safety of darinaparsin monotherapy in patients with relapsed or refractory PTCL conducted in Japan, Korea, Taiwan, and Hong Kong. (CT.gov Identifier: NCT02653976).
Solasia plans to present the results of the study at an international academic conference to be held in the near future.
About peripheral T-cell lymphoma (PTCL)
Please visit at https://solasia.co.jp/en/pipeline/sp-02.html
About Solasia
Please visit at https://solasia.co.jp/en/
/////////////Darinaparsin, Darvias, JAPAN 2022, APPROVALS 2022, PMDA, ダリナパルシン , Zinapar, ZIO-101, DMAs(III)G, clarinaparsin, UNII-9XX54M675G, SP-02L, Orphan Drug
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