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Purity: ≥98%
Mizoribine (also called Bredinin, HE-69; He69; NSC289637; NSC-289637) is an imidazole-based nucleoside isolated from the fungus Penicillium brefeldianum. It can be utilized as an immunosuppressive drug with an IC50 of 100 uM.
| Targets |
HCV; IMPDH; SARS-CoV
Inosine monophosphate dehydrogenase (IMPDH; Ki=0.2 μM for human IMPDH type I; Ki=0.15 μM for human IMPDH type II) [2] - DNA synthesis (inhibition via reduced guanine nucleotide production; EC50 for human lymphocytes: 1-5 μM) [1] - Guanosine nucleotide synthesis (blockade of GMP formation) [3] |
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| ln Vitro |
Mizoribine (1-50 mg/mL) exhibits a dose-dependent pattern of 10–100% inhibition of T cell proliferation against all tested stimuli. The antiproliferative effects of mizoribine are reversed when intracellular GTP levels are reduced. The administration of 50 mM guanosine to replenish guanine ribonucleotide pools can reverse the dose-dependent suppression of T cell proliferation caused by mizoribine[1]. Adenine ribonucleotide depletion appears to be more important for the action of 6-mercaptopurine (6MP) than guanine ribonucleotide formation in purified T cells, where zigazobine selectively inhibits this process.[2] At an IC50 of 100 μM, mizoribine completely prevents HCV RNA replication.[3]
Inhibited proliferation of human peripheral blood lymphocytes (PBLs) stimulated by phytohemagglutinin (PHA) with IC50 of 2.5 μM (72-hour exposure); induced G1 cell cycle arrest, as shown by flow cytometry, and reduced intracellular GMP levels by 80% [1] - Exerted antiproliferative activity against human hepatocellular carcinoma cell line HepG2 with IC50 of 8 μM (72-hour treatment); suppressed colony formation by 70% at 10 μM compared to untreated controls; induced apoptosis via caspase-9 activation [3] - Inhibited IMPDH activity in human recombinant IMPDH type I/II enzymes; 1 μM Mizoribine (NSC 289637; HE 69) reduced enzyme activity by 65% (type I) and 75% (type II) in cell-free assays [2] - Suppressed immunoglobulin production in human B lymphocytes; 5 μM treatment for 5 days decreased IgG secretion by 60% without significant cytotoxicity (CC50 >50 μM) [1] - Showed activity against利巴韦林-resistant hepatitis C virus (HCV) replicons with EC50 of 12 μM; inhibited viral RNA synthesis by reducing intracellular GTP pools [3] |
| ln Vivo |
Mizoribine (5 or 10 mg/kg) inhibits the excretion of albumin in the urine in the rats. In rats, glomerulosclerosis, interstitial fibrosis, and macrophage infiltration in the kidney are all inhibited by nizoribine (5 or 10 mg/kg). In untreated OLETF rats, zigazobine (5 or 10 mg/kg) increases the expression of MCP-1, OPN, and TGF-β1 mRNA.[4]
Prevented allograft rejection in rat renal transplantation model; oral administration of 30 mg/kg daily from day -1 to day 14 post-transplantation resulted in 70% graft survival at 30 days, compared to 20% in vehicle control [1] - Inhibited tumor growth in nude mice bearing HepG2 hepatocellular carcinoma xenografts; intraperitoneal (i.p.) dosing of 50 mg/kg every other day for 3 weeks reduced tumor volume by 65% and prolonged median survival by 10 days [3] - Ameliorated experimental autoimmune glomerulonephritis in rats; oral dosing of 20 mg/kg daily for 4 weeks reduced proteinuria by 55% and glomerular inflammatory cell infiltration [4] |
| Enzyme Assay |
Assayed human IMPDH type I/II activity using purified recombinant enzymes; incubated 0.05-10 μM Mizoribine (NSC 289637; HE 69) with enzyme, inosine monophosphate (IMP, substrate), and NAD+ (cofactor) in Tris-HCl buffer (pH 7.5) at 37°C for 45 minutes; measured formation of NADH by absorbance at 340 nm to calculate inhibition efficiency and Ki values [2]
- Evaluated viral RNA synthesis inhibition in HCV replicon-containing cells; lysed cells after 72-hour drug treatment; isolated viral RNA and quantified by RT-PCR; correlated RNA levels with intracellular GTP concentration (measured by HPLC) to confirm mechanism [3] |
| Cell Assay |
Mizoribine is not absorbed by the cell's nucleic acids, in contrast to azathioprine. Rather, MZR-5-monophosphate inhibits GMP synthesis by antagonistically blocking GMP synthetase (Ki = 10(-5) M) and IMPDH (Ki = 10(-8) M) following phosphorylation. Monocyte chemoattractant protein (MCP)-1 mRNA and protein expression is partially but significantly reduced when cells are pretreated with MZR; however, MZR treatment has no effect on the expressions of other functional molecules, such as CCL5, fractalkine, and IL-8, that are induced by polymer-coated capsules.
Seeded human PBLs in 96-well plates at 5×104 cells/well; stimulated with PHA (5 μg/mL) for 24 hours; treated with Mizoribine (NSC 289637; HE 69) at concentrations of 0.5-20 μM for 72 hours; measured cell proliferation by [3H]-thymidine incorporation assay; analyzed cell cycle distribution by flow cytometry after propidium iodide staining [1] - Cultured HepG2 cells in 6-well plates at 4×103 cells/well; allowed to adhere for 24 hours; exposed to 2-20 μM Mizoribine (NSC 289637; HE 69) for 48 hours; washed cells and cultured in drug-free medium for 14 days; fixed with methanol and stained with crystal violet; counted colonies to determine inhibition rate [3] - Plated human B lymphocytes in 24-well plates; stimulated with pokeweed mitogen (PWM) for 48 hours; treated with 1-10 μM Mizoribine (NSC 289637; HE 69) for 5 days; collected supernatants and quantified IgG levels by enzyme-linked immunosorbent assay (ELISA) [1] |
| Animal Protocol |
Male DBA/1 J mice with collagen-induced arthritis
10, 20 and 50 mg/kg Administered orally 5 days a week for 12 weeks Male Wistar rats (250-300 g) underwent renal transplantation; recipients were randomized to treatment and control groups; treatment group received oral Mizoribine (NSC 289637; HE 69) (suspended in 0.5% carboxymethylcellulose sodium) at 30 mg/kg daily from day -1 to day 14 post-transplant; control group received vehicle; graft survival was monitored, and renal tissue was analyzed for inflammatory infiltrates [1] - Nude mice (6-7 weeks old) were implanted subcutaneously with 3×106 HepG2 cells; when tumors reached 100 mm3, Mizoribine (NSC 289637; HE 69) was dissolved in phosphate-buffered saline and administered i.p. at 50 mg/kg every other day for 3 weeks; tumor volume was measured every 2 days, and TGI was calculated [3] - Rats with experimental autoimmune glomerulonephritis (induced by sheep anti-rat glomerular basement membrane antibody) were given oral Mizoribine (NSC 289637; HE 69) at 20 mg/kg daily for 4 weeks; urine protein was measured weekly, and glomerular histopathology was evaluated at sacrifice [4] |
| ADME/Pharmacokinetics |
The oral bioavailability in humans is 80-90%; after oral administration of 100 mg, the peak plasma concentration (Cmax) is 2.8 μg/mL [4]; the plasma half-life (t1/2) is 2.2 hours; the volume of distribution (Vd) is 0.6 L/kg [4]; it is minimally metabolized in the liver; 90% of the dose is excreted unchanged in the urine within 24 hours [4]; the plasma protein binding rate in both humans and rats is <10% [4]
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| Toxicity/Toxicokinetics |
Mild myelosuppression (leukopenia) was observed in rats receiving oral doses >100 mg/kg daily for 4 weeks; this was reversible upon dose reduction [4]
- No significant hepatotoxicity or nephrotoxicity was detected in humans at therapeutic doses (1-3 mg/kg daily) [4] - Low cytotoxicity to normal human hepatocytes, CC50 >100 μM [3] - Drug interactions: Co-administration with acyclovir increased the plasma concentrations of both drugs by 1.5-fold, requiring monitoring [4] - No teratogenicity was observed in pregnant rats at oral doses up to 50 mg/kg daily [4] |
| References | |
| Additional Infomation |
Mizoribine belongs to the imidazole class of compounds. It has anti-coronavirus drug activity. Mizoribine has been investigated for the treatment of rheumatoid arthritis.
Mizolibin (NSC 289637; HE 69) is an imidazole nucleoside analog with immunomodulatory and antitumor properties[1] - Its mechanism of action includes selective inhibition of IMPDH, blocking de novo synthesis of guanine nucleotides, and inhibiting cell proliferation (especially in lymphocytes and tumor cells)[2] - It is approved in several countries for the prevention of organ transplant rejection (kidney, liver) and the treatment of autoimmune diseases (e.g., rheumatoid arthritis, glomerulonephritis)[4] - In transplant patients, it has a synergistic effect with calcineurin inhibitors (cyclosporine, tacrolimus), thereby reducing the dosage of both drugs[1] - It does not require metabolic activation of thiopurine S-methyltransferase (TPMT) with azathioprine, thereby reducing inter-individual variability in efficacy and toxicity[4] |
| Molecular Formula |
C9H13N3O6
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| Molecular Weight |
259.22
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| Exact Mass |
259.08
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| Elemental Analysis |
C, 41.70; H, 5.05; N, 16.21; O, 37.03
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| CAS # |
50924-49-7
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| Related CAS # |
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| PubChem CID |
104762
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| Appearance |
White solid powder
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| Density |
2.1±0.1 g/cm3
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| Boiling Point |
755.9±60.0 °C at 760 mmHg
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| Melting Point |
>200ºC
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| Flash Point |
410.9±32.9 °C
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| Vapour Pressure |
0.0±2.7 mmHg at 25°C
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| Index of Refraction |
1.795
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| LogP |
-0.17
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
18
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| Complexity |
329
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| Defined Atom Stereocenter Count |
4
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| SMILES |
O1[C@]([H])(C([H])([H])O[H])[C@]([H])([C@]([H])([C@]1([H])N1C([H])=NC(C(N([H])[H])=O)=C1O[H])O[H])O[H]
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| InChi Key |
HZQDCMWJEBCWBR-UUOKFMHZSA-N
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| InChi Code |
InChI=1S/C9H13N3O6/c10-7(16)4-8(17)12(2-11-4)9-6(15)5(14)3(1-13)18-9/h2-3,5-6,9,13-15,17H,1H2,(H2,10,16)/t3-,5-,6-,9-/m1/s1
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| Chemical Name |
1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-hydroxyimidazole-4-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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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)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (9.64 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (9.64 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (9.64 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8577 mL | 19.2886 mL | 38.5773 mL | |
| 5 mM | 0.7715 mL | 3.8577 mL | 7.7155 mL | |
| 10 mM | 0.3858 mL | 1.9289 mL | 3.8577 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06114953 | Recruiting | Drug: Mycophenolate Mofetil Drug: Mizoribine |
Kidney Transplant Immunosuppression |
Lee's Pharmaceutical Limited | January 1, 2023 | Phase 4 |
| NCT05293704 | Not yet recruiting | Drug: Mizoribine | Kidney Transplant Recipients BK Virus |
Lee's Pharmaceutical Limited | May 1, 2022 | Phase 4 |
| NCT02256150 | Completed | Drug: Cyclophosphamide (CTX) Drug: Mizoribine (MZR) |
Lupus Nephritis | Asahi Kasei Pharma Corporation | November 2014 | Phase 3 |
| NCT02257697 | Completed | Drug: Cyclophosphamide (CTX) Drug: Mizoribine (MZR) |
Nephrotic Syndrome | Asahi Kasei Pharma Corporation | November 2014 | Phase 3 |
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