Sulindac Sulfide
[CAS# 49627-27-2]

Identification

• Classification: Biochemical >> Inhibitor >> Proteases >> Gamma-secretase inhibitor
• Name: Sulindac Sulfide
• Synonyms: 2-[(3Z)-6-fluoro-2-methyl-3-[(4-methylsulfanylphenyl)methylidene]inden-1-yl]acetic acid
• Molecular Formula: C₂₀H₁₇FO₂S
• Molecular Weight: 340.41
• CAS Registry Number: 49627-27-2
• EC Number: 256-403-9
• SMILES: CC\1=C(C2=C(/C1=C\C3=CC=C(C=C3)SC)C=CC(=C2)F)CC(=O)O

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Boiling point: 526.3±50.0 ºC 760 mmHg (Calc.)^*
• Flash point: 272.1±30.1 ºC (Calc.)^*
• Index of refraction: 1.653 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Discovory and Applicatios

Sulindac sulfide is the active metabolite of the nonsteroidal anti-inflammatory drug (NSAID) sulindac. It belongs to the indene class of compounds and has the molecular formula C₂₀H₁₇FO₂S. Structurally, it features an indene ring system with a fluorine atom, a sulfinyl group that has been reduced to a sulfide, and a substituted phenylacetic acid side chain. Sulindac sulfide is known for its potent anti-inflammatory, analgesic, and antipyretic properties and plays a central role in the therapeutic effects of sulindac.

Sulindac itself is a prodrug, which means it is pharmacologically inactive until it undergoes metabolic conversion in the body. After oral administration, sulindac is absorbed and then reduced in the liver to sulindac sulfide, which is the pharmacologically active form. This transformation enhances the drug’s safety and bioavailability by minimizing gastrointestinal side effects common to other NSAIDs. The sulfoxide-to-sulfide reduction is mediated by hepatic enzymes and is a key step in the drug’s mechanism of action.

Sulindac sulfide works primarily by inhibiting the activity of cyclooxygenase (COX) enzymes—specifically COX-1 and COX-2. These enzymes are responsible for the conversion of arachidonic acid into prostaglandins, which are lipid compounds that mediate inflammation, pain, and fever. By reducing the synthesis of prostaglandins, sulindac sulfide exerts its anti-inflammatory and analgesic effects. The compound’s ability to inhibit both COX isoforms contributes to its effectiveness, although COX-1 inhibition is often associated with gastrointestinal side effects in long-term NSAID use.

Beyond its anti-inflammatory action, sulindac sulfide has attracted scientific interest for its potential chemopreventive effects. Studies have indicated that sulindac and its metabolites, particularly sulindac sulfide, may reduce the incidence of colorectal adenomas and other premalignant lesions. This effect is thought to be related not only to COX inhibition but also to COX-independent mechanisms such as the induction of apoptosis and inhibition of cell proliferation in certain tumor cells. These observations have led to research on sulindac sulfide as a possible agent in cancer prevention or adjunct therapy, especially in familial adenomatous polyposis (FAP) and other hereditary cancer syndromes.

Sulindac sulfide has been extensively studied in vitro and in animal models to explore its anti-neoplastic properties. It appears to modulate signaling pathways such as Wnt/β-catenin and nuclear factor-κB (NF-κB), which are involved in cell growth and survival. However, its clinical use remains primarily as an anti-inflammatory drug, and its role in oncology remains investigational.

Analytical techniques for detecting and quantifying sulindac sulfide in biological samples include high-performance liquid chromatography (HPLC), mass spectrometry (MS), and ultraviolet (UV) spectroscopy. These methods are essential for pharmacokinetic studies and therapeutic monitoring. The compound’s metabolic profile has also been well-characterized, including its interconversion with sulindac sulfone, another sulindac metabolite that lacks COX-inhibitory activity but has its own potential biological effects.

In terms of safety, sulindac sulfide shares the typical risk profile of NSAIDs. Adverse effects may include gastrointestinal irritation, renal impairment, and cardiovascular events, particularly with long-term use. However, the prodrug nature of sulindac helps limit these risks by reducing direct exposure of the gastrointestinal tract to the active metabolite.

In summary, sulindac sulfide is a metabolically activated form of sulindac responsible for its anti-inflammatory and analgesic effects. As a COX inhibitor with additional biological activity, it plays a significant role in both therapeutic use and ongoing research into chemoprevention and anticancer strategies. Its well-defined metabolic pathway, pharmacological action, and chemical stability have made it an important compound in the study of NSAID pharmacology.

References

2023. Effects of acidic non-steroidal anti-inflammatory drugs on human cytochrome P450 4A11 activity: Roles of carboxylic acid and a sulfur atom in potent inhibition by sulindac sulfide. Chemico-Biological Interactions, 382.
DOI: 10.1016/j.cbi.2023.110644

2024. Sulindac exhibits anti-proliferative and anti-invasive effects in uterine serous carcinoma cells. Journal of Cancer Research and Clinical Oncology, 150(8).
DOI: 10.1007/s00432-024-05926-9

2021. Design, synthesis, and biological evaluation of novel sulindac derivatives as partial agonists of PPARγ with potential anti-diabetic efficacy. European Journal of Medicinal Chemistry, 223.
DOI: 10.1016/j.ejmech.2021.113542