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| Targets |
NF-κB mTOR
beta‑amyloid (Abeta) and beta‑amyloid precursor protein (APP). TML-6 functions by impeding the synthesis of APP and its proteolytic product Abeta. It also modulates several key signaling pathways: it upregulates Apo E, suppresses NF‑kappaB (reducing inflammation), suppresses mTOR, and activates the antioxidant transcription factor Nrf2. |
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| ln Vitro |
TML-6 (0.65–5.24 µg/mL; for 24 hours) increases the expression of ApoE protein while decreasing that of APP and phospho-NF-κB. TML-6 suppresses phospho-mTOR, which in turn inhibits the mTOR signaling pathway[1]. With an IC50 of 4.19 µg/mL (8 μM), TML-6 (0.31, 0.63, 2.5, 5, 10, 20 μM; 24 h) exhibits minimal cytotoxicity in Huh-7 cells at concentrations below 5 μM[1]. In N2a/APPswe cells, TML-6 (1.05, 2.09, 3.14, 4.19 μg/mL; 24 h) dose-dependently decreases the production of Aβ40 and Aβ42 between 1.05, 2.09, and 3.14 μg/mL (equivalent to 2, 4 and 6 μM)[1]. TML-6 has the ability to activate the Nrf2 gene transcriptionally in a dose-dependent manner; the maximum activity is observed at 1.32 µg/mL[1].
In vitro, TML-6 has been shown to inhibit the synthesis of both the beta‑amyloid precursor protein and the pathogenic beta‑amyloid (Abeta) peptide. It upregulates Apo E and increases the activity of the anti-oxidative Nrf2 gene, while suppressing the inflammatory NF-kappaB and the cell-growth mTOR pathways. These combined anti-inflammatory, antioxidant, and anti-amyloid effects make it a multi-targeted candidate for Alzheimer's disease (AD) research. |
| ln Vivo |
Treatment with TML-6 (diet; 150 mg/kg/day; for four months) significantly improves learning and reduces Aβ in the brain and the microglial activation marker Iba-1[1]. The T1/2, Cmax, and AUC of TML-6 (oral; 150 mg/kg) are 1.27 hours, 35.9 ng/mL, and 177 ng·hr/mL, respectively[1].
In vivo, TML-6 is an orally active curcumin derivative that ameliorates inflammation and can be used to study Alzheimer's disease. By inhibiting Abeta synthesis, reducing inflammation (via NF-kappaB suppression), and activating Nrf2-mediated antioxidant defenses, it is expected to improve cognitive function in preclinical models of AD. Detailed in vivo activity data (e.g., efficacy in transgenic mouse models) are not provided in the summary but are implied by its designation as an AD research agent. |
| Enzyme Assay |
A cell‑free assay for TML-6 can be designed to measure its effect on beta‑amyloid (Abeta) aggregation. The Abeta1-42 peptide (25 uM) is incubated in a 50 mM Tris-HCl buffer (pH 7.4) with 150 mM NaCl and 0.05% sodium azide at 37degC for 24-48 hours to allow fibril formation. Thioflavin T (ThT) is added to a final concentration of 10 uM. Varying concentrations of TML-6 (0.1-100 uM) are co-incubated with the Abeta peptide. The fluorescence of ThT (ex 440 nm, em 490 nm) is measured over time. A reduction in ThT fluorescence compared to the control (Abeta only) indicates inhibition of Abeta fibril formation. For anti-inflammatory activity, a cell‑free NF‑kappaB p50/p65 transcription factor assay kit can be used. The DNA-binding activity of NF‑kappaB is measured by incubating a nuclear extract from cells stimulated with TNF-alpha (pre-treated with TML-6) with a biotinylated NF‑kappaB consensus oligonucleotide in a 96-well plate. After binding, the complex is detected by a colorimetric ELISA assay. A reduction in NF‑kappaB binding indicates inhibition.
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: Huh-7 cells Tested Concentrations: 0.65, 1.31, 1.96, 2.61, 3.93, 5.24 µg/mL Incubation Duration:For 24 hrs (hours) Experimental Results: diminished the amyloid precursor protein (APP) protein expression level by 60 % and diminished the level of phosphorylated NF-κB by about 50% at a dose of 1.96 µg/mL after 24 h treatment. Induced the protein expression level of ApoE by approximately 44% at a dose of 2.62 µg/mL. For cellular assays, BV-2 microglial cells or primary astrocytes are seeded in 96‑well plates (20,000 cells/well) in DMEM/F-12/10% FBS. The next day, cells are pre-treated with varying concentrations of TML-6 (1-50 uM) for 2 hours, then stimulated with lipopolysaccharide (LPS, 1 ug/mL) for 24 hours. Supernatants are collected to measure pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) by ELISA. Cell lysates can be prepared for Western blot to measure levels of iNOS and COX-2. Reactive oxygen species (ROS) generation is measured using the fluorescent probe DCFH-DA. For Nrf2 activation, cells are treated with TML-6 for 4-6 hours, and nuclear extracts are prepared. The amount of Nrf2 translocated to the nucleus is measured by ELISA using a specific Nrf2 transcription factor kit. To measure Abeta synthesis, a human neuroblastoma cell line (e.g., SH-SY5Y) overexpressing APP can be used. Cells are treated with TML-6 for 24 hours, and the level of Abeta1-40 and Abeta1-42 in the conditioned media is measured by a sensitive ELISA. |
| Animal Protocol |
Animal/Disease Models: Six-month-old 3xTg (mutations: APPKM670 /671NL, MAPTP301L and PSEN1M146V) AD transgenic mice[1]
Doses: 150 mg/kg Route of Administration: Diet; daily; for four months Experimental Results: Improved the learning behaviors, Dramatically suppressed the Aβ levels and Iba-1 expression in the brain of 3xTg AD transgenic mice. Animal/Disease Models: SD rats[1] Doses: 150 mg/kg (pharmacokinetic/PK Analysis) Route of Administration: Oral Experimental Results: Had a T1/2 of 1.27 hrs (hours), a Cmax of 35.9 ng/mL and an AUC of 177 ng• hr/mL. In vivo studies are performed in a mouse model of Alzheimer's disease, such as the 5xFAD or APP/PS1 transgenic mice. Male and female mice (6-8 months old) are used when Abeta plaques are established. TML-6 is formulated in a vehicle (e.g., 0.5% methylcellulose or corn oil) and administered orally at a dose of 25-100 mg/kg once daily for 4-8 weeks. Control mice receive vehicle. At the end of the treatment period, cognitive function is assessed using the Morris water maze (MWM) to measure learning and memory. Mice are trained for 5 days, and a probe trial is performed on day 6. The latency to find the hidden platform and the time spent in the target quadrant are recorded. After behavioral testing, mice are euthanized, and brains are collected. One hemisphere is fixed for histology to quantify Abeta plaque load (using Thioflavin S or 6E10 antibody). The other hemisphere is homogenized for biochemical analysis, including measurement of Abeta40/42 levels by ELISA, inflammatory markers (TNF-alpha, IL-1beta) by ELISA, and markers of oxidative stress (e.g., malondialdehyde, MDA). The levels of Nrf2 and its downstream target, HO-1, in brain tissue are also measured by Western blot. |
| ADME/Pharmacokinetics |
As an orally available compound, TML-6 is designed for oral administration. It is soluble in DMSO (≥50 mg/mL). Its specific half-life and bioavailability have not been detailed in the provided search summaries, but it is characterized as orally active. Its curcumin-like structure suggests it may have moderate metabolic stability.
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| Toxicity/Toxicokinetics |
Toxicity data are not detailed. As an orally active curcumin derivative, it is likely to be well-tolerated at the doses used in research. Curcumin and its derivatives are generally considered safe, with no significant acute toxicity reported. Standard safety precautions for handling research chemicals should be followed.
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| References | |
| Additional Infomation |
TML-6 is an orally available curcumin derivative with multi-targeted activity against key Alzheimer's disease pathologies, including the inhibition of Abeta synthesis, activation of Nrf2, and suppression of NF-kappaB and mTOR. CAS: 1462868-88-7.
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| Molecular Formula |
C30H37NO7
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|---|---|
| Molecular Weight |
523.617289304733
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| Exact Mass |
523.257
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| CAS # |
1462868-88-7
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| Related CAS # |
TML-6-d3;2673270-28-3
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| PubChem CID |
72705569
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| Appearance |
Off-white to yellow solid powder
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| LogP |
4.4
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
14
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| Heavy Atom Count |
38
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| Complexity |
783
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(CC(C(/C=C/C1C=CC(=C(C=1)OC)OC)=O)(C(/C=C/C1C=CC(=C(C=1)OC)OC)=O)C)N(CC)CC
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| InChi Key |
UWVCYNXVZRDWSD-UNZYHPAISA-N
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| InChi Code |
InChI=1S/C30H37NO7/c1-8-31(9-2)29(34)20-30(3,27(32)16-12-21-10-14-23(35-4)25(18-21)37-6)28(33)17-13-22-11-15-24(36-5)26(19-22)38-7/h10-19H,8-9,20H2,1-7H3/b16-12+,17-13+
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| Chemical Name |
(E)-6-(3,4-dimethoxyphenyl)-3-[(E)-3-(3,4-dimethoxyphenyl)prop-2-enoyl]-N,N-diethyl-3-methyl-4-oxohex-5-enamide
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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 Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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) |
DMSO: 120 mg/mL (229.17 mM)
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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 | 1.9098 mL | 9.5489 mL | 19.0978 mL | |
| 5 mM | 0.3820 mL | 1.9098 mL | 3.8196 mL | |
| 10 mM | 0.1910 mL | 0.9549 mL | 1.9098 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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