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Purity: ≥98%
SW-100 (SW100), a tetrahydroquinoline-based compound, is a novel, potent, brain penetrant and selective histone deacetylase 6 (HDAC6) inhibitor (IC50 = 2.3 nM) with neuroprotective effects.HDAC6 exhibits selectivity that is at least 1000 times greater than that of all other HDAC isozymes. The ability of SW-100 to cross the blood-brain barrier is noticeably better. Since there are currently no effective treatments or cures for fragile X syndrome (FXS), disease-modifying therapies are required. SW-100 can enhance memory function in an FXS mouse model using Fmr1-/-mice. This tiny molecule exhibits at least a thousand-fold selectivity over all other class I, II, and IV HDAC isoforms, good brain penetration, and low-nanomolar potency for the inhibition of HDAC6 (IC50 = 2.3 nM). Furthermore, SW-100 selectively restores the reduced levels of acetylated α-tubulin in the hippocampus of Fmr1-/- mice by inhibiting the α-tubulin deacetylase domain of HDAC6 (CD2), which in turn increases α-tubulin acetylation in cells without affecting histone acetylation. Finally, by improving a number of memory and learning deficits in Fmr1-/-mice, SW-100 models the intellectual deficiencies linked to FXS, which is compelling evidence to support the development of HDAC6-based treatments for this uncommon illness.
| Targets |
HDAC1 (IC50 = 5.23 μM); HDAC2 (IC50 = 32.8 μM); HDAC3 (IC50 = 29.5 μM); HDAC4 (IC50 = 10.9 μM); HDAC5 (IC50 = 4.07 μM); HDAC6 (IC50 = 2.3 nM); HDAC7 (IC50 = 4.55 μM); HDAC8 (IC50 = 3.72 μM); HDAC9 (IC50 = 3.46 μM); HDAC10 (IC50 = 26.2 μM); HDAC11 (IC50 = 5.72 μM)
SW-100 is a highly selective histone deacetylase 6 (HDAC6) inhibitor. The reported IC₅₀ value for HDAC6 is 2.3 nM. It demonstrates at least 1000-fold to 10000-fold selectivity over all other class I, II, and IV HDAC isoforms, including HDAC1 (IC₅₀ = 5.3 µM), HDAC8 (IC₅₀ = 3.7 µM), and others. [1] |
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| ln Vitro |
SW-100 (0.01-10 µM; 48 hours) exhibits a clear, dose-dependent increase in the levels of acetylated α-tubulin[1].
SW-100 exhibited an IC₅₀ of 279 nM for full-length HDAC6 and 97 nM for the CD2 domain of HDAC6 in a cellular NanoBRET target engagement assay. [1] Treatment of HEK293 cells with SW-100 led to a dose-dependent increase in acetylated α-tubulin levels, similar to the positive control NexA. It increased acetylated α-tubulin levels starting at concentrations as low as 10 nM. [1] In N2a neuronal cells, treatment with 1 µM SW-100 increased the ratio of acetylated α-tubulin to total α-tubulin (>8-fold compared to vehicle), while inducing only a modest change (<1.5-fold) in the levels of acetylated histone H3 to histone H4, demonstrating functional selectivity for tubulin over histone deacetylation. [1] |
| ln Vivo |
SW-100 (20 mg/kg; i.p.; twice a day for two days) improves a number of memory and learning deficits, such as novel object recognition, temporal ordering, and coordinate and categorical spatial processing of Fragile X syndrome[1].
Intraperitoneal administration of SW-100 (20 mg/kg, twice daily) to Fmr1⁻/⁻ mice (a model of Fragile X Syndrome) for 2 days, with additional injections on test days, ameliorated several cognitive impairments. It reversed deficits in coordinate spatial processing, categorical spatial processing, novel object recognition, and temporal order memory tasks. The performance of treated Fmr1⁻/⁻ mice was not significantly different from vehicle-treated wild-type mice in these tasks. The treatment did not alter the performance of wild-type mice. [1] SW-100 treatment (same dosing regimen) significantly increased the impaired levels of acetylated α-tubulin in the hippocampus of Fmr1⁻/⁻ mice, restoring them towards wild-type levels. No significant effect on acetylated α-tubulin levels was observed in the hippocampus of wild-type mice. [1] |
| Enzyme Assay |
HDAC inhibition assays were performed using human full-length recombinant HDAC1-11 isoforms. Fluorogenic peptide substrates were used: a peptide derived from p53 (RHKK(Ac)AMC) for HDAC1, 2, 3, 6, 10, and 11; a peptide containing a trifluoroacetylated lysine (Ac-LGK(TFA)-AMC) for HDAC4, 5, 7, and 9; and a peptide derived from p53 (RHK(Ac)K(Ac)AMC) for HDAC8. Reactions were carried out in buffer containing Tris-HCl, NaCl, KCl, MgCl₂, and BSA at pH 8.0. Test compounds were pre-incubated with the enzyme for 5-10 minutes before substrate addition. The reaction was incubated for 2 hours at 30°C, then quenched with a developer. Fluorescence was measured kinetically, and endpoint readings were used for IC₅₀ determination using a sigmoidal dose-response curve fit. [1]
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| Cell Assay |
Cell Line: HEK293 cells
Concentration: 0.01, 0.1, 1, 10 µM Incubation Time: 48 hours Result: Showed obvious increase in the acetylated α-tubulin levels in a dose-dependent manner. For α-tubulin acetylation studies in HEK293 cells, cells were plated and treated with SW-100 at concentrations of 10 nM, 100 nM, 1 µM, and 10 µM for 24 hours. Cells were then lysed, and protein concentrations were determined. Samples were subjected to SDS-PAGE, transferred to PVDF membranes, and probed with antibodies against acetylated α-tubulin and total α-tubulin. Signal was detected by chemiluminescence and quantified by densitometry. [1] For α-tubulin/histone acetylation studies in N2a cells, cells were treated with 1 µM or 10 nM SW-100. Cells were collected, and total histone proteins were extracted. Protein samples were analyzed by Western blot using antibodies against acetylated α-tubulin, total α-tubulin, acetylated histone H3 (Lys9/Lys14), and total histone H4. [1] For NanoBRET target engagement assays, HEK293 cells stably expressing NanoLuc-HDAC6 (full-length or CD2 domain) or HDAC1-NanoLuc were used. Cells were incubated with a cell-permeable SAHA-based tracer at specified concentrations (100 nM for full-length HDAC6, 250 nM for HDAC6-CD2, 1000 nM for HDAC1). Serially diluted SW-100 was added and allowed to equilibrate for 2 hours. After adding NanoGlo substrate and extracellular NanoLuc inhibitor, luminescence was measured at 450 nm (donor) and >610 nm (acceptor). Competitive displacement data were fitted to a three-parameter curve to determine IC₅₀ values. [1] |
| Animal Protocol |
8-10 weeks old C57BL/6 mice (Fmr1-/- mice)[1]
20 mg/kg Intraperitoneal injection; twice a day for two days For efficacy studies in Fmr1⁻/⁻ mice, adult male wild-type and Fmr1⁻/⁻ mice (8-10 weeks old) were used. SW-100 was dissolved in a formulation of 10% DMSO, 40% PEG-400, and 50% saline to a concentration of 4 mg/mL. The compound was administered via intraperitoneal injection at a dose of 20 mg/kg body weight, twice daily for 2 consecutive days. Additional injections were given 1 hour prior to cognitive testing on the third and fourth days. [1] Cognitive tasks (coordinate spatial processing, categorical spatial processing, novel object recognition, and temporal order memory) were conducted over two days. Mice were habituated to the testing room. Objects and apparatus were cleaned with 70% ethanol between sessions. Exploration times were scored from video recordings by an investigator blinded to genotype and treatment. [1] For acetylated α-tubulin analysis in brain tissue, mice were treated with the same dosing regimen (20 mg/kg, twice daily for 2 days, plus injection on test days). Hippocampi were dissected, homogenized in lysis buffer, and centrifuged. Protein concentrations were determined, and samples were analyzed by Western blot using antibodies against acetylated α-tubulin and total α-tubulin. [1] |
| ADME/Pharmacokinetics |
In a preliminary pharmacokinetic study of wild-type C57BL/6 male mice, the brain-to-plasma ratio was 2.44 1 hour after a single intraperitoneal injection of SW-100 (20 mg/kg) and 4.54 4 hours after administration. [1]
SW-100 exhibits low metabolic stability in human and mouse liver microsomes (half-life <10 min). Its half-life is also short in human and mouse hepatocytes (<30 min). [1] In an hERG inhibition assay in HEK293 cells, the compound had an IC₅₀ > 10 µM. At a concentration of 10 µM, the compound showed low inhibition of major human cytochrome P450 isoenzymes (1A2, 2C9, 2C19, 2D6, 3A4) (<25%). [1] |
| Toxicity/Toxicokinetics |
In the Ames mutagenicity assay, using four Salmonella typhimurium strains (TA98, TA100, TA1535, TA1537) and one Escherichia coli strain (WP2 uvrA), all results were negative in the presence or absence of metabolic activation (S9 mixture). [1]
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| References | |
| Additional Infomation |
SW-100 is a tetrahydroquinoline-based phenylhydroxyoxime compound designed to enhance its brain permeability compared to earlier HDAC6 inhibitors, such as tubastatin A (TubA). The increased brain uptake is attributed to its lower calculated pKₐ value (2.91) of its basic cap group, resulting in a favorable P-glycoprotein efflux ratio of 0.51 in MDCK-MDR1 cells. [1] In a mouse model of Fragile X syndrome, its mechanism of action is thought to be the selective inhibition of HDAC6, leading to increased levels of α-tubulin acetylation in the brain. This is presumably intended to improve impaired microtubule-dependent transport in the disease, thereby alleviating cognitive deficits. [1] This study positions SW-100 as a novel, highly selective HDAC6 inhibitor capable of penetrating the blood-brain barrier, with the potential to treat cognitive impairment associated with Fragile X syndrome and other neurodegenerative diseases. [1]
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| Molecular Formula |
C17H17CLN2O2
|
|---|---|
| Molecular Weight |
316.782083272934
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| Exact Mass |
316.1
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| Elemental Analysis |
C, 64.46; H, 5.41; Cl, 11.19; N, 8.84; O, 10.10
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| CAS # |
2126744-35-0
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| Related CAS # |
2126744-35-0
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| PubChem CID |
130345472
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
3.3
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
22
|
| Complexity |
385
|
| Defined Atom Stereocenter Count |
0
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| InChi Key |
MNAYBFFSFQRSIT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C17H17ClN2O2/c18-15-7-8-16-14(10-15)2-1-9-20(16)11-12-3-5-13(6-4-12)17(21)19-22/h3-8,10,22H,1-2,9,11H2,(H,19,21)
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| Chemical Name |
4-[(6-chloro-3,4-dihydro-2H-quinolin-1-yl)methyl]-N-hydroxybenzamide
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| Synonyms |
SW-100; SW 100; SW100
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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) |
DMSO: ≥ 125 mg/mL (~394.6 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.57 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 20.8 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: ≥ 2.08 mg/mL (6.57 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 20.8 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: ≥ 2.08 mg/mL (6.57 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 | 3.1568 mL | 15.7838 mL | 31.5676 mL | |
| 5 mM | 0.6314 mL | 3.1568 mL | 6.3135 mL | |
| 10 mM | 0.3157 mL | 1.5784 mL | 3.1568 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.
 ACS Chem Neurosci.2019 Mar 20;10(3):1679-1695. |
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