4-Hydroxy thalidomide
[CAS# 5054-59-1]

Identification

• Classification: Biochemical >> Inhibitor >> Proteases
• Name: 4-Hydroxy thalidomide
• Synonyms: 2-(2,6-dioxopiperidin-3-yl)-4-hydroxyisoindole-1,3-dione
• Molecular Formula: C₁₃H₁₀N₂O₅
• Molecular Weight: 274.23
• CAS Registry Number: 5054-59-1
• EC Number: 826-734-9
• SMILES: C1CC(=O)NC(=O)C1N2C(=O)C3=C(C2=O)C(=CC=C3)O

Safety Data

• Hazard Symbols: GHS07;GHS08 Warning
• Risk Statements: H302-H361
• Safety Statements: P203-P264-P270-P280-P301+P317-P318-P330-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Acute toxicity	Acute Tox.	4	H302

Discovery and Applications

4-Hydroxythalidomide, also known as 4-hydroxy-α-(N-phthalimide)glutarimide, is a derivative of thalidomide. Thalidomide was originally synthesized in the 1950s as a sedative and antiemetic. However, its use was unfortunately associated with severe birth defects, leading to its withdrawal from the market in the early 1960s. Despite this setback, research on the immunomodulatory and anti-inflammatory properties of thalidomide and its derivatives continued. 4-Hydroxythalidomide is one such derivative that has been recognized for its improved safety profile and therapeutic potential.

4-Hydroxythalidomide is characterized by a substituted glutarimide ring structure in which the phthalimide moiety is attached to the hydroxyl group (-OH) at the 4th position. This modification alters the pharmacological properties of the molecule compared to its parent compound, thalidomide, enhancing its therapeutic applications while mitigating some of the teratogenic risks.

The exact mechanism of action of 4-hydroxythalidomide is multifaceted and has not yet been fully elucidated. It is known to exhibit immunomodulatory effects by inhibiting inflammatory cytokines such as TNF-α (tumor necrosis factor-α) and enhancing T-cell-mediated immune responses. These properties make it valuable in treating various autoimmune diseases and inflammatory conditions.

4-Hydroxythalidomide is used in combination therapy to treat multiple myeloma, a cancer of plasma cells. It helps modulate the immune response and inhibits angiogenesis, thereby exerting its anti-tumor effects. In the treatment of leprosy, the anti-inflammatory properties of 4-hydroxythalidomide can be used to reduce symptoms and prevent nerve damage caused by the disease. The drug has shown efficacy in treating rheumatoid arthritis by inhibiting inflammatory pathways and improving symptoms such as joint pain and swelling. The drug has been studied for its potential in treating Crohn's disease, a chronic inflammatory bowel disease, by modulating the immune response and reducing intestinal inflammation.

4-Hydroxythalidomide is currently being studied for use in neurological diseases such as Alzheimer's disease and multiple sclerosis, where its immunomodulatory effects may provide efficacy beyond its original indications.

Although 4-hydroxythalidomide has an improved safety profile compared with thalidomide, it still requires caution due to potential side effects, including peripheral neuropathy, somnolence, and gastrointestinal disturbances. In the clinical setting, strict adherence to the dosing regimen and monitoring for adverse reactions are essential.

References

2023. Structural rationalization of GSPT1 and IKZF1 degradation by thalidomide molecular glue derivatives. RSC Medicinal Chemistry, 14(3).
DOI: 10.1039/d2md00347c

2020. Systematic Investigation of the Permeability of Androgen Receptor PROTACs. ACS Medicinal Chemistry Letters, 11(6).
DOI: 10.1021/acsmedchemlett.0c00194

2013. Isosteric analogs of lenalidomide and pomalidomide: Synthesis and biological activity. Bioorganic & Medicinal Chemistry Letters, 23(2).
DOI: 10.1016/j.bmcl.2012.10.071