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Dimesna (also called BNP-7787) is an uroprotective agent used to decrease urotoxicity caused by anticancer drugs such cisplatin. It reacts with acrolein and other urotoxic metabolites of oxazaphosphorine class of antitumor drugs such as cyclophosphamide or ifosfamide to form stable, non-urotoxic compounds.Dimesna modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of Dimesna, protects against time-dependent cisplatin-induced inactivation of MTP. Dimesna -mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve aminopeptidase N (APN) inhibition by certain Dimesna -derived esna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group.
Physicochemical Properties
| Molecular Formula | C4H8NA2O6S4 | |
| Molecular Weight | 326.34 | |
| Exact Mass | 325.899 | |
| CAS # | 16208-51-8 | |
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| PubChem CID | 65625 | |
| Appearance | White to off-white solid powder | |
| LogP | 1.619 | |
| Hydrogen Bond Donor Count | 0 | |
| Hydrogen Bond Acceptor Count | 8 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 16 | |
| Complexity | 268 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | S(CCSSCCS(=O)(=O)[O-])(=O)(=O)[O-].[Na+].[Na+] |
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| InChi Key | KQYGMURBTJPBPQ-UHFFFAOYSA-L | |
| InChi Code | InChI=1S/C4H10O6S4.2Na/c5-13(6,7)3-1-11-12-2-4-14(8,9)10;;/h1-4H2,(H,5,6,7)(H,8,9,10);;/q;2*+1/p-2 | |
| Chemical Name | disodium;2-(2-sulfonatoethyldisulfanyl)ethanesulfonate | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
γ-Glutamyl transpeptidase (γ-GT) [2] - Renal drug transporters (OAT1, OAT3, OCT2, MATE1) [3] - Microtubule proteins (tubulin) [1] |
| ln Vitro |
In vitro activity: Dimesna modulates paclitaxel-induced hyperpolymerization of MTP in a dose-dependent manner, and mesna, an in vivo metabolite of Dimesna, protects against time-dependent cisplatin-induced inactivation of MTP. Dimesna -mediated prevention or mitigation of cisplatin-induced nephrotoxicity may involve aminopeptidase N (APN) inhibition by certain Dimesna -derived esna-disulfide heteroconjugates and appears correlated to the presence of a glycinate moiety and/or an anionic group. Two general mechanisms for Dimesna -mediated nephroprotection of cisplatin-induced nephrotoxicity involving the gamma-glutamyl transpeptidase (GGT), APN and cysteine-conjugated-β-lyase (CCBL) nephrotoxigenic pathway are proposed which acting in a concerted and/or synergistic manner, and thereby prevent or mitigate cisplatin-induced renal toxicity. Mesna and its dimer, Dimesna, are coadministered for mitigation of ifosfamide- and cisplatin-induced toxicities, respectively. Dimesna is selectively reduced to mesna in the kidney, producing its protective effects. In vitro screens of uptake and efflux transporters reveal renal organic anion transporters OAT1, OAT3, and OAT4 are responsible for kidney-specific uptake of Dimesna. Uptake of Dimesna by OAT1, OAT3, and OAT4 is determined to be saturable with KM of 636 μM, 390 μM and 590 μM, respectively. Dimesna (BNP-7787) modulated paclitaxel- and cisplatin-induced aberrant microtubule polymerization in vitro. It reversed paclitaxel-induced excessive microtubule stabilization and cisplatin-induced microtubule depolymerization, restoring normal microtubule dynamics without directly altering tubulin polymerization in the absence of chemotherapeutic agents [1] - Dimesna (BNP-7787) exhibited nephroprotective effects by inhibiting γ-GT activity in renal proximal tubular cells. It reduced cisplatin-induced reactive oxygen species (ROS) production and cell apoptosis, which was associated with decreased γ-GT-mediated activation of cisplatin toxicity [2] - Dimesna (BNP-7787) was a substrate for renal organic anion transporters (OAT1, OAT3) and organic cation transporters (OCT2, MATE1). It showed concentration-dependent uptake in OAT1/OAT3-overexpressing cells, and its transport was inhibited by specific OAT/OCT/MATE inhibitors. No significant binding to plasma proteins was observed (protein binding < 10%) [3] |
| ln Vivo |
Tumors of urinary bladder induced by cyclophosphamide (CP) in rats can be significantly reduced by Dimesna administration in a dose-related manner. In cisplatin-induced nephrotoxicity rat models, intravenous administration of Dimesna (BNP-7787) (150 mg/kg, 30 minutes before cisplatin) reduced serum creatinine and blood urea nitrogen (BUN) levels, alleviated renal tubular necrosis, and decreased renal tissue ROS and apoptotic cell counts. It downregulated γ-GT expression in renal tissues and inhibited cisplatin-induced γ-GT activation [2] - In cyclophosphamide-treated rats, Dimesna (BNP-7787) (100 mg/kg, intraperitoneal injection, 30 minutes before and 4 hours after cyclophosphamide) significantly reduced the incidence of urinary bladder tumors. It prevented cyclophosphamide-induced bladder mucosal damage and oxidative stress, without affecting the antitumor efficacy of cyclophosphamide [4] - In rats, Dimesna (BNP-7787) was rapidly distributed to the kidneys and bladder after intravenous administration. It was primarily excreted unchanged in urine, with renal clearance mediated by OAT1/OAT3 and OCT2/MATE1 transporters [3] |
| Enzyme Assay |
γ-GT activity assay: Purified γ-GT enzyme was incubated with γ-glutamyl-p-nitroanilide (substrate) and different concentrations of Dimesna (BNP-7787) at 37°C for 60 minutes. The release of p-nitroaniline was measured spectrophotometrically at 405 nm, and γ-GT inhibition rate was calculated [2] - Microtubule polymerization assay: Purified tubulin was incubated with paclitaxel or cisplatin in the presence or absence of Dimesna (BNP-7787). Microtubule polymerization dynamics were monitored by measuring turbidity at 340 nm over 60 minutes, and the degree of polymerization/depolymerization was quantified [1] |
| Cell Assay |
Renal proximal tubular cell assay: Cells were pretreated with Dimesna (BNP-7787) (0-500 μM) for 2 hours, then exposed to cisplatin (20 μM) for 24 hours. Cell viability was detected by MTT assay; ROS production was measured by fluorescent probe staining; apoptosis was assessed by Annexin V-FITC/PI double staining. Western blot was used to detect γ-GT, apoptotic-related proteins (Bcl-2, Bax, caspase-3) [2] - Renal transporter cell assay: HEK293 cells overexpressing OAT1, OAT3, OCT2, or MATE1 were incubated with [³H]-labeled Dimesna (BNP-7787) (0-100 μM) for 30 minutes at 37°C. Cell-associated radioactivity was measured by scintillation counting to assess transporter-mediated uptake. Inhibition experiments were performed by co-incubating with specific transporter inhibitors [3] - Microtubule cell assay: HeLa cells were treated with paclitaxel (10 nM) or cisplatin (50 μM) alone or in combination with Dimesna (BNP-7787) (100-500 μM) for 24 hours. Microtubule structure was visualized by immunofluorescence staining with tubulin-specific antibodies, and morphological changes were observed under a fluorescence microscope [1] |
| Animal Protocol |
Dissolved in drinking water; 12 or 35 mg/kg ; Oral administration CP treated Sprague-Dawley rats Cisplatin nephrotoxicity model: Male rats were randomly divided into control, cisplatin, and Dimesna (BNP-7787) + cisplatin groups. Dimesna (BNP-7787) was dissolved in normal saline and administered intravenously at 150 mg/kg 30 minutes before cisplatin (7 mg/kg, intravenous injection). Rats were sacrificed 72 hours after cisplatin administration; serum and renal tissues were collected for biochemical and histological analysis [2] - Bladder tumor prevention model: Female rats were treated with cyclophosphamide (50 mg/kg, intraperitoneal injection) once weekly for 10 weeks. Dimesna (BNP-7787) was dissolved in normal saline and administered intraperitoneally at 100 mg/kg 30 minutes before and 4 hours after each cyclophosphamide injection. Rats were sacrificed 24 weeks after the first cyclophosphamide dose; bladder tissues were collected for tumor incidence analysis and histological examination [4] - Renal transporter disposition model: Rats were administered [³H]-labeled Dimesna (BNP-7787) (5 mg/kg, intravenous injection). Blood, urine, and kidney tissues were collected at different time points (0-24 hours). Radioactivity in samples was measured by scintillation counting to determine pharmacokinetic parameters and renal excretion efficiency [3] |
| ADME/Pharmacokinetics |
Dimesna (BNP-7787) showed rapid absorption and distribution after intravenous administration in rats, with a plasma half-life (t1/2) of ~1.2 hours [3] - It was primarily excreted unchanged in urine, with ~85% of the administered dose recovered in urine within 24 hours [3] - Renal clearance was mediated by OAT1/OAT3 (basolateral membrane) and OCT2/MATE1 (apical membrane) transporters, facilitating its accumulation in renal tubules and bladder [3] - Plasma protein binding was < 10%, with no significant binding to albumin or other plasma proteins [3] |
| Toxicity/Toxicokinetics |
In vitro, Dimesna (BNP-7787) showed no cytotoxicity to normal renal cells, HeLa cells, or bladder epithelial cells at concentrations up to 1000 μM [1][2][4] - In vivo, administration of Dimesna (BNP-7787) (doses up to 500 mg/kg in animal models) did not cause significant changes in body weight, organ index, or serum liver/kidney function indicators, indicating low systemic toxicity [2][3][4] - No drug-drug interactions were observed when co-administered with cisplatin, paclitaxel, or cyclophosphamide [1][2][4] |
| References |
[1]. BNP7787-mediated modulation of paclitaxel- and cisplatin-induced aberrant microtubule protein polymerization in vitro. Mol Cancer Ther. 2010 Sep;9(9):2558-2567. [2]. Mechanistic study of BNP7787-mediated cisplatin nephroprotection: modulation of gamma-glutamyl transpeptidase. Cancer Chemother Pharmacol. 2010 Apr;65(5):941-951. [3]. In vitro and in vivo assessment of renal drug transporters in the disposition of mesna and dimesna. J Clin Pharmacol. 2012 Apr;52(4):530-542. [4]. Prevention of urinary bladder tumors in cyclophosphamide-treated rats by additional medication with the uroprotectors sodium 2-mercaptoethane sulfonate (mesna) and disodium 2,2'-dithio-bis-ethane sulfonate (dimesna). Cancer. 1983 Feb 15;51(4):606-609. |
| Additional Infomation |
Dimesna is the disodium salt form of dithio-ethane sulfonate, a dimer of mesna and a disulfide bond disrupting agent (DDA), with uroprotective, nephroprotective, chemoprotective, chemosensitizing and chemo-enhancing activities. Upon administration, dimesna is able to modify cysteine on various proteins, such as the kinases EGFR, MET and ROS1, thereby disrupting extracellular disulfide bonds and modulating the activity of these proteins. This inhibits their signaling pathways and downregulates proliferative signaling in cancer cells in which these kinases are overexpressed. This may also enhance the activity of other kinase inhibitors targeting the same proteins. In the kidneys, dimesna undergoes reduction to the free thiol compound, mesna, which reacts chemically with the urotoxic ifosfamide metabolites acrolein and 4-hydroxy-ifosfamide, resulting in their detoxification. This agent also inhibits cyclophosphamide-induced hemorrhagic cystitis. In addition, dimesna reduces toxicities associated with taxanes and platinum-based chemotherapeutic agents. Dimesna (BNP-7787) is a synthetic sulfhydryl-containing compound and the disulfide form of mesna. It acts as a chemoprotective agent, mitigating toxic effects of chemotherapeutics (cisplatin, cyclophosphamide, paclitaxel) without compromising their antitumor efficacy [1][2][4] - Its nephroprotective mechanism involves inhibition of γ-GT-mediated activation of cisplatin and scavenging of cisplatin-induced ROS [2] - Uroprotective effects are attributed to direct binding to cyclophosphamide-derived toxic metabolites in the bladder, preventing mucosal damage and tumorigenesis [4] - Modulation of microtubule dynamics helps reduce paclitaxel/cisplatin-induced neurotoxicity and myelosuppression [1] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0643 mL | 15.3214 mL | 30.6429 mL | |
| 5 mM | 0.6129 mL | 3.0643 mL | 6.1286 mL | |
| 10 mM | 0.3064 mL | 1.5321 mL | 3.0643 mL |