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Purity: ≥98%
Marimastat (formerly aslo known as BB2516; BB-2516; TA2516; TA-2516) is a broad-spectrum, oral bioactive inhibitor of matrix metalloprotease (MMP) that may have anticancer effects. With IC50s of 3 nM, 5 nM, 6 nM, 9 nM, and 13 nM, respectively, it inhibits MMP-9/2/14/7. Clinical trials on marimastat were investigated, but they were abandoned because of poor results.
| Targets |
MMP-3 (IC50 = 3 nM); MMP-1 (IC50 = 5 nM); MMP-2 (IC50 = 6 nM); MMP-14 (IC50 = 9 nM); MMP-7 (IC50 = 13 nM)
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| ln Vitro |
Marimastat (100 nM) significantly reduces MMP14 expression in GBM39, GBM43, U251, and U87 tumor cells. Marimastat specifically prevents glioma cell growth while having no effect on healthy human astrocytes (NHA).[3]
Marimastat early down-regulates Notch target gene expression, including Hes1 and Hes5.[4] |
| ln Vivo |
Marimastat (150 mg/kg/day, p.o.) delivered by an osmotic pump dramatically reduces cervical lymph node metastasis and MMP-2 activation in an orthotopic oral squamous cell carcinoma implantation model. Additionally, the marimastat group exhibits a significantly higher survival rate than the control group.[5]
Marimastat inhibits the cystic expansion of PCK cholangiocytes and decreases the MMP hyperactivity of polycystic human and rat cholangiocytes. Hepatic cystogenesis and fibrosis are inhibited in 8-week-old PCK rats when marimastat is administered chronically.[6]
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| Enzyme Assay |
For one hour at 37°C, recombinant human MMP2 is activated with 1 mM 4-aminophenylmercuric acetate. The cleavage rates of 1-methoxycoumarin-4-yl, the quenched fluorescent MMP substrate, were measured. Gly-Leu-acetyl-Pro-Leu-[3-(2,4-dinitrophenyl)-L-2,3-diaminoproprionyl] At 37°C, measurements of Ala-Arg-NH2 are made in 96-well fluorimetry plates. In the presence of increasing inhibitor concentrations, 100 mM Tris-HCl (pH 7.5), 100 mM NaCl, 10 mM CaCl2, and 0.05% Brij 35 were tested with 320 nm excitation and 405 nm emission filters. GraphPad Prism 5.0 software is used for IC50 calculations and curve fitting.
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| Cell Assay |
Marimastat attenuates tumor invasion significantly in co-cultures of tumor spheroids derived from human glioma cell lines U251 and GaMG with RBA at concentrations of 10 μM. Marimastat (10 μM) completely inhibits cell growth at 50 μM over six days and significantly reduces cell proliferation by 54%. Furthermore, marimastat (10 μM) 65% inhibits the growth of U251 spheroid.
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| Animal Protocol |
Using a trochar needle, 2 mm2 of established SCC-1 tissue is subcutaneously injected into the flanks of three-month-old female naked mice. The tumors are treated when they reach a diameter of 5–6 mm. The mice are segregated at random into groups of eight and given one of four treatments: (1) control, (2) marimastat on its own, (3) cisplatin + radiation combined, and (4) marimastat + cisplatin + radiation joint. An osmotic pump containing dimethylsulfoxide (DMSO) is given to each animal for a period of 14 days, serving as a control for the vehicle and pump. Using the same osmotic pump that contains 200 μL of marimastat with DMSO, animals receiving marimastatreatment receive a daily dose of 8.7 mg/kg ten days after treatment starts. On days 8, 12, 16, and 20, lead-shielded animals receive 8 Gy of 60Co radiation to the exposed tumor, split into 4 fractions. Because 7.5 Gy (7,500 rad) has been demonstrated in earlier studies to inhibit tumor growth without being a curative dose, a dose of 8 Gy was selected. Four intraperitoneal doses of cisplatin (3 mg/kg) are administered to the animals one hour prior to each radiation fraction. For 32 days, tumors are measured every two weeks. Using mouse weight, potential treatment toxicity is tracked. In each treatment group, the tumor size (surface area equal to the product of the two largest diameters) and regression rates are measured. Tumors are removed for immunohistochemistry after 32 days. Day 32 was selected to enable statistical analysis of data obtained from surviving animals, as a result of the death of control group animals and the euthanasia of animals exhibiting clinical signs of illness.
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| References | |
| Additional Infomation |
Marimastat is a secondary carboxamide resulting from the foraml condensation of the carboxy group of (2R)-2-[(1S)-1-hydroxy-2-(hydroxyamino)-2-oxoethyl]-4-methylpentanoic acid with the alpha-amino group of N,3-dimethyl-L-valinamide. It has a role as an antineoplastic agent and a matrix metalloproteinase inhibitor. It is a secondary carboxamide and a hydroxamic acid.
Used in the treatment of cancer, Marmiastat is an angiogenesis and metastasis inhibitor. As an angiogenesis inhibitor it limits the growth and production of blood vessels. As an antimetatstatic agent it prevents malignant cells from breaching the basement membranes. Marimastat is an orally-active synthetic hydroxamate with potential antineoplastic activity. Marimastat covalently binds to the zinc(II) ion in the active site of matrix metalloproteinases (MMPs), thereby inhibiting the action of MMPs, inducing extracellular matrix degradation, and inhibiting angiogenesis, tumor growth and invasion, and metastasis. This agent may also inhibit tumor necrosis factor-alpha converting enzyme (TACE), an enzyme involved in tumor necrosis factor alpha (TNF-alpha) production that may play a role in some malignancies as well as in the development of arthritis and sepsis. (NCI04) Drug Indication For the treatment of various cancers Mechanism of Action Marimastat is a broad spectrum matrix metalloprotease inhibitor. It mimics the peptide structure of natural MMP substrates and binds to matrix metalloproteases, thereby preventing the degradation of the basement membrane by these proteases. This antiprotease action prevents the migration of endothelial cells needed to form new blood vessels. Inhibition of MMPs also prevents the entry and exit of tumor cells into existing blood cells, thereby preventing metastasis. Pharmacodynamics Used in the treatment of cancer, it is an angiogenesis and metastasis inhibitor. As an angiogenesis inhibitor it limits the growth and production of blood vessels. As an antimetatstatic agent it prevents malignant cells from breaching the basement membranes. |
| Molecular Formula |
C15H29N3O5
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| Molecular Weight |
331.41
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| Exact Mass |
331.21
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| Elemental Analysis |
C, 54.36; H, 8.82; N, 12.68; O, 24.14
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| CAS # |
154039-60-8
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| Related CAS # |
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| PubChem CID |
119031
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Melting Point |
148℃
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| Index of Refraction |
1.499
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| LogP |
-0.16
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| Hydrogen Bond Donor Count |
5
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
23
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| Complexity |
431
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| Defined Atom Stereocenter Count |
3
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| SMILES |
O([H])[C@]([H])(C(N([H])O[H])=O)[C@]([H])(C(N([H])[C@]([H])(C(N([H])C([H])([H])[H])=O)C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
OCSMOTCMPXTDND-OUAUKWLOSA-N
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| InChi Code |
InChI=1S/C15H29N3O5/c1-8(2)7-9(10(19)13(21)18-23)12(20)17-11(14(22)16-6)15(3,4)5/h8-11,19,23H,7H2,1-6H3,(H,16,22)(H,17,20)(H,18,21)/t9-,10+,11-/m1/s1
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| Chemical Name |
(2R,3S)-N-[(2S)-3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl]-N',3-dihydroxy-2-(2-methylpropyl)butanediamide
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| Synonyms |
BB 2516; TA-2516; Marimastat; BB-2516; BB2516; TA2516; TA 2516
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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 (7.54 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 (7.54 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 (7.54 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 50% DMSO+PBS: 30mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0174 mL | 15.0871 mL | 30.1741 mL | |
| 5 mM | 0.6035 mL | 3.0174 mL | 6.0348 mL | |
| 10 mM | 0.3017 mL | 1.5087 mL | 3.0174 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 |
| NCT00003011 | Completed | Drug: marimastat Drug: Placebo |
Lung Cancer | NCIC Clinical Trials Group | January 31, 1997 | Phase 3 |
| NCT00002911 | Completed | Drug: marimastat | Lung Cancer | ILEX Oncology Services, Incorporated |
December 1996 | Phase 3 |
| NCT00003010 | Completed | Drug: marimastat | Breast Cancer | Eastern Cooperative Oncology Group |
December 2, 1997 | Phase 3 |
| NCT00261391 | Completed | Drug: Marimastat | Vascular Anomalies | Boston Children's Hospital | October 2000 | Phase 1 |
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