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| Targets |
ND-336 targets matrix metalloproteinase 2 (MMP-2, gelatinase A), MMP-9 (gelatinase B), and MMP-14 (membrane type 1-MMP). MMP-2 and MMP-9 are gelatinases that degrade type IV collagen, a major component of the basement membrane, and are involved in cell migration, angiogenesis, and tissue remodeling. MMP-14 is a membrane-anchored MMP that activates pro-MMP-2 and degrades extracellular matrix components. ND-336 inhibits these MMPs with Ki values of 85 nM for MMP-2, 150 nM for MMP-9, and 120 nM for MMP-14. The compound's selectivity for MMP-2, MMP-9, and MMP-14 over other MMP isoforms is a key feature that allows researchers to study the specific roles of these gelatinases and MT1-MMP in various biological processes without the confounding effects of broad-spectrum MMP inhibition.
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| ln Vitro |
In vitro, ND-336 selectively inhibits the enzymatic activity of MMP-2, MMP-9, and MMP-14. The compound's inhibitory activity is concentration-dependent, with Ki values of 85 nM for MMP-2, 150 nM for MMP-9, and 120 nM for MMP-14. In cellular assays, ND-336 has been shown to reduce the migration and invasion of cells that depend on MMP-2 or MMP-9 activity for these processes. The compound also inhibits the activation of pro-MMP-2 by MMP-14, further contributing to its effects on gelatinase activity. In addition to its effects on cell migration, ND-336 modulates inflammatory responses in immune cells, reducing the production of pro-inflammatory cytokines and chemokines. The compound's selectivity for gelatinases over other MMPs has been confirmed in enzyme inhibition assays using a panel of recombinant MMPs.
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| ln Vivo |
By lowering inflammation, promoting angiogenesis, and re-epithelializing the wound, ND-336 hastens the healing of diabetic wounds and reverses the underlying pathology [1]. ND-336 (0.05–0.01 mg; topically applied; once daily for 14 days) expedites the healing of diabetic wounds [1].
In vivo, ND-336 has been shown to promote diabetic wound healing in mouse models. In a streptozotocin-induced diabetic mouse model, topical or systemic administration of ND-336 accelerates wound closure, reduces the inflammatory response, and promotes angiogenesis and re-epithelialization. The compound's effects are attributed to the inhibition of MMP-2, MMP-9, and MMP-14, which are upregulated in diabetic wounds and contribute to excessive matrix degradation, impaired angiogenesis, and delayed healing. By inhibiting these MMPs, ND-336 reduces the inflammatory response, allowing for more efficient tissue repair. In addition to its effects on wound healing, ND-336 has been studied in models of cancer and inflammatory diseases, where the inhibition of gelatinases and MT1-MMP may have therapeutic benefits. |
| Enzyme Assay |
The non-cellular assay for ND-336 involves measuring the inhibition of MMP enzymatic activity using fluorogenic or colorimetric substrates. Recombinant human MMP-2, MMP-9, or MMP-14 is incubated with a specific fluorogenic substrate (such as a peptide containing a quenched fluorophore) in the presence of varying concentrations of ND-336. The cleavage of the substrate by the MMP results in an increase in fluorescence, which is monitored over time using a fluorescence plate reader. The inhibition of enzymatic activity by ND-336 is calculated as a percentage of the control (without inhibitor), and the Ki or IC50 is determined from concentration-response curves. The selectivity of ND-336 for MMP-2, MMP-9, and MMP-14 over other MMP isoforms (such as MMP-1, MMP-3, MMP-7, MMP-8, MMP-12, and MMP-13) is assessed by performing similar assays with each MMP isoform.
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| Cell Assay |
The cellular assay for ND-336 involves treating cultured cells with the compound and assessing its effects on cell migration, invasion, and MMP activity. Cells that express MMP-2, MMP-9, or MMP-14 (such as cancer cells, fibroblasts, or endothelial cells) are seeded in Transwell chambers or wound healing assays. ND-336 is added to the culture medium at various concentrations, and cell migration or invasion is measured after a defined incubation period. The inhibition of cell migration by ND-336 is calculated as a percentage of the control. In addition, the activity of MMP-2 and MMP-9 in the cell culture supernatant is measured by gelatin zymography, and the activation of pro-MMP-2 by MMP-14 is assessed by Western blotting. The effects of ND-336 on cell viability and proliferation are assessed to ensure that the observed effects are not due to non-specific cytotoxicity.
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| Animal Protocol |
Animal/Disease Models: Female diabetic db/db mice [1]
Doses: 0.05, 0.025, and 0.01 mg Route of Administration: Topical application; one time/day for 14 days Experimental Results: Patients treated with ND-322 healed faster than vehicle Treated patients 1.2 to 1.6 times faster. The in vivo animal studies for ND-336 typically use the streptozotocin (STZ)-induced diabetic wound healing model in mice. Diabetes is induced by intraperitoneal injection of STZ, and after diabetes is confirmed, full-thickness excisional wounds are created on the back of the mice. ND-336 is administered topically (applied to the wound) or systemically (by intraperitoneal injection) at various doses (typically 1-10 mg/kg) daily. Wound closure is monitored by measuring the wound area at regular intervals (every 2-3 days) using digital calipers or image analysis. At the end of the study, wound tissues are collected for histopathological examination (H&E and Masson's trichrome staining), for measurement of inflammatory markers (such as TNF-α, IL-1β, and IL-6), and for assessment of angiogenesis (by CD31 immunostaining) and re-epithelialization. The efficacy of ND-336 is compared to that of vehicle-treated controls and to standard wound healing agents. |
| ADME/Pharmacokinetics |
ND-336 hydrochloride has a molecular weight of 371.90 g/mol and a molecular formula of C₁₆H₁₈ClNO₃S₂. The compound is soluble in DMSO and other organic solvents and should be stored as a powder at -20°C, protected from light and moisture. Its pharmacokinetic properties, including oral bioavailability and tissue distribution, have been characterized in preclinical studies. The compound is typically formulated in appropriate vehicles for topical or systemic administration.
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| Toxicity/Toxicokinetics |
ND-336 hydrochloride is generally well-tolerated in preclinical studies at the doses used for wound healing experiments. However, as an MMP inhibitor, it may affect normal tissue remodeling processes, and long-term effects on tissue repair and immune function have not been fully characterized. Comprehensive toxicology data are limited to preclinical findings. ND-336 is not approved for clinical use and is strictly a research compound.
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| References |
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| Additional Infomation |
ND-336 hydrochloride is a selective inhibitor of MMP-2, MMP-9, and MMP-14 that has been developed as a research tool for studying the roles of gelatinases and MT1-MMP in tissue repair, inflammation, and cancer. Its selectivity for specific MMP isoforms over other MMPs makes it a valuable tool for dissecting the distinct functions of different MMPs in various biological processes. The compound's ability to promote diabetic wound healing in mice by reducing inflammation and promoting angiogenesis and re-epithelialization highlights its potential as a lead compound for the development of new wound healing therapies. ND-336 continues to be studied for its therapeutic potential and as a research tool for MMP biology.
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| Molecular Formula |
C16H18CLNO3S2
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| Molecular Weight |
371.894
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| Exact Mass |
371.041
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| CAS # |
1807453-83-3
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| Related CAS # |
(R)-ND-336;2252493-33-5
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| PubChem CID |
132285189
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
23
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| Complexity |
447
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1C(S1)CS(=O)(=O)C2=CC=C(C=C2)OC3=CC=C(C=C3)CN.Cl
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| InChi Key |
DRGIZFGSEKSFIC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H17NO3S2.ClH/c17-9-12-1-3-13(4-2-12)20-14-5-7-16(8-6-14)22(18,19)11-15-10-21-15;/h1-8,15H,9-11,17H2;1H
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| Chemical Name |
[4-[4-(thiiran-2-ylmethylsulfonyl)phenoxy]phenyl]methanamine;hydrochloride
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| Synonyms |
ND336; ND 336; ND-336
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6890 mL | 13.4448 mL | 26.8897 mL | |
| 5 mM | 0.5378 mL | 2.6890 mL | 5.3779 mL | |
| 10 mM | 0.2689 mL | 1.3445 mL | 2.6890 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.
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