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Purity: ≥98%
(S)-Thalidomide is the S-enantiomer of thalidomide, which is an immunomodulatory agent and the model drug of the thalidomide class of medications. It is primarily used to treat certain cancers (such as multiple myeloma) and a leprosy complication. The German pharmaceutical company Grunenthal first introduced it as a sedative and immunomodulatory agent in the 1950s. It is also being studied for its potential to treat the symptoms of numerous cancers. Thalidomide is now frequently used as a building block for PROTACs (Proteolysis Targeting Chimeras), which serve as ligands for the E3 ubiquitin ligase cereblon. The PROTAC technology makes use of hetero-bifunctional small molecules, one end of which attracts an E3 ubiquitin ligase and the other of which interacts with the target protein. A CRBN-DDB1-Cul4A complex is an E3 ubiquitin ligase that is inhibited by thalidomide. Thalidomide is an effective costimulator of primary human T cells in vitro. When combined with stimulation through the T cell receptor complex, it promotes the proliferation of T cells through interleukin 2 and the production of interferon gamma.
| Targets |
Cereblon; Apoptosis; E3 ligase
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| ln Vitro |
(S)-Thalidomide treatment results in a reduction in cell viability in U266 cells with an IC50 of 362 μM[1].
(S)-Thalidomide treatment increased apoptosis in a dose-dependent manner in U266 cells[1]. Genes involved in apoptosis and angiogenesis have altered expression profiles, but the apoptotic genes have undergone the most significant changes. In particular, there is a two-fold reduction in I-B kinase expression, which is accompanied by a four-fold reduction in NF-B expression. The Bax:Bcl-2 ratio is raised by (S)-thalidomide, which also raises I-kB protein levels and lowers NF-kB activity. When combined with other cytotoxic agents, (S)-Thalidomide dramatically reduces Bcl-2 expression, which raises the possibility of enhancing the cytotoxic effect[1]. |
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| ln Vivo |
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| Cell Assay |
s-Thalidomide has proven efficacy in multiple myeloma. Although it has both antiangiogenic and pro-apoptotic effects, its primary mode of therapeutic action remains unclear. We have investigated the changes to the expression of genes involved with these cellular processes following culture with s-thalidomide in the U266 MM cell line. Cells were cultured with s-thalidomide (0-1000 microM), and cell parameters, including apoptosis, were assessed on day 3. RNA was extracted from cells cultured for 24 h at the IC(50) concentration of s-thalidomide, and changes to gene expression were investigated by microarray methodologies. A reduction in cell viability was observed in U266 cells cultured with s-thalidomide (IC(50): 362 microM), which were mirrored by significant increases in apoptosis (for example, 200 microM on day 3: 40.3+/-3.1% vs. 3.2+/-0.4% on day 0; P<0.001). There were changes in the expression profile of genes involved in angiogenesis and apoptosis, but the changes were most dramatic in the apoptotic genes. In particular, the expression of I-kappaB kinase was decreased by two-fold, which was associated with a four-fold decrease in NF-kappaB expression. These data correlated with immunoblotting analyses, which showed significant increases in I-kappaB protein levels and decreased NF-kappaB activity. Additionally, the Bax : Bcl-2 ratio was significantly increased. Our data suggest that both angiogenic and apoptotic genes and proteins are affected by s-thalidomide. Additionally, a dramatic decrease in Bcl-2 expression with s-thalidomide suggests a possible enhancement of cytotoxic effect if combined with other cytotoxic agents[1].
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| Animal Protocol |
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| ADME/Pharmacokinetics |
Metabolism / Metabolites
(-)-thalidomide has known human metabolites that include 5-hydroxy-thalidomide, 5'-Hydroxythalidomide, and (-)-thalidomide arene oxide. |
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| Toxicity/Toxicokinetics |
mouse LD50 oral 700 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Nature., 215(296), 1967 [PMID:6059519]
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| References |
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| Additional Infomation |
(S)-thalidomide is a 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione that has S-configuration at the chiral centre. It has a role as a teratogenic agent. It is an enantiomer of a (R)-thalidomide.
Twenty years after the thalidomide disaster in the late 1950s, Blaschke et al. reported that only the (S)-enantiomer of thalidomide is teratogenic. However, other work has shown that the enantiomers of thalidomide interconvert in vivo, which begs the question: why is teratogen activity not observed in animal experiments that use (R)-thalidomide given the ready in vivo racemization ("thalidomide paradox")? Herein, we disclose a hypothesis to explain this "thalidomide paradox" through the in-vivo self-disproportionation of enantiomers. Upon stirring a 20% ee solution of thalidomide in a given solvent, significant enantiomeric enrichment of up to 98% ee was observed reproducibly in solution. We hypothesize that a fraction of thalidomide enantiomers epimerizes in vivo, followed by precipitation of racemic thalidomide in (R/S)-heterodimeric form. Thus, racemic thalidomide is most likely removed from biological processes upon racemic precipitation in (R/S)-heterodimeric form. On the other hand, enantiomerically pure thalidomide remains in solution, affording the observed biological experimental results: the (S)-enantiomer is teratogenic, while the (R)-enantiomer is not.[4] |
| Molecular Formula |
C13H10N2O4
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|---|---|
| Molecular Weight |
258.23
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| Exact Mass |
258.064
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| Elemental Analysis |
C, 60.47; H, 3.90; N, 10.85; O, 24.78
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| CAS # |
841-67-8
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| Related CAS # |
Thalidomide;50-35-1;Thalidomide-d4;1219177-18-0;(R)-Thalidomide;2614-06-4
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| PubChem CID |
92142
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| Appearance |
Off-white to light brown solid powder
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| Density |
1.503g/cm3
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| Boiling Point |
509.7ºC at 760 mmHg
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| Melting Point |
269-271ºC
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| Flash Point |
262.1ºC
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| Index of Refraction |
1.646
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| LogP |
0.354
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
19
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| Complexity |
449
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C1CC(=O)NC(=O)C1N2C(=O)C3=CC=CC=C3C2=O
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| InChi Key |
UEJJHQNACJXSKW-VIFPVBQESA-N
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| InChi Code |
InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)/t9-/m0/s1
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| Chemical Name |
2-[(3S)-2,6-dioxopiperidin-3-yl]isoindole-1,3-dione
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| Synonyms |
(S)-Thalidomide; NSC91730; NSC 91730; (S)-Thalidomide; (-)-Thalidomide; 841-67-8; (S)-(-)-thalidomide; l-Thalidomide; S-(-)-Thalidomide; S-Thalidomide; Thalidomide, (-)-; NSC-91730; l-Thalidomide
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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: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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) |
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| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.8725 mL | 19.3626 mL | 38.7252 mL | |
| 5 mM | 0.7745 mL | 3.8725 mL | 7.7450 mL | |
| 10 mM | 0.3873 mL | 1.9363 mL | 3.8725 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 |
| NCT00040937 | Completed | Biological: filgrastim Drug: thalidomide |
Multiple Myeloma | SWOG Cancer Research Network | June 2002 | Phase 2 |
| NCT01485224 | Completed | Drug: Thalidomide | Epistaxis Hereditary Hemorrhagic Telangiectasia |
IRCCS Policlinico S. Matteo | November 2011 | Phase 2 |
| NCT00142116 | Completed | Drug: Rituximab Drug: Thalidomide |
Waldenstrom's Macroglobulinemia Lymphoplasmacytic Lymphoma |
Steven P. Treon, MD, PhD | May 2003 | Phase 2 |
| NCT00602511 | Completed | Drug: Bortezomib Drug: Thalidomide |
Multiple Myeloma | Nordic Myeloma Study Group | October 2007 | Phase 3 |
| NCT00367185 | Completed | Drug: Thalidomide | Multiple Myeloma | University Hospital, Lille | May 2000 | Phase 3 |
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