23288-49-5

Basic information

• Product Name: Probucol
• Synonyms: PROBUCOL;4,4’-((1-methylethylidene)bis(thio))bis(2,6-bis(1,1-dimethylethyl)-pheno;biphenabid;bisbid;bisphenabid;dh581;4,4'-ISOPROPYLIDINEDITHIO-BIS-(2,6-DI-TERT-BUTYL)PHENOL;4-({1-[(4-hydroxy-3,5-di-t-butylphenyl)thio]-1-methylethyl}thio)-2,6-di-t-butylphenol
• CAS NO: 23288-49-5
• Molecular Formula: C₃₁H₄₈O₂S₂
• Molecular Weight: 516.84
• EINECS: 245-560-9
• Product Categories: Cardiovascular;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds;API;LORELCO;Isolabel;Cardiovascular APIs
• Mol File: 23288-49-5.mol
• Article Data: 12

Chemical Properties

• Melting Point: 126-128°C
• Boiling Point: 571.58°C (rough estimate)
• Flash Point: 264.9 °C
• Appearance: White Solid
• Density: 1.0008 (rough estimate)
• Vapor Pressure: 1.46E-12mmHg at 25°C
• Refractive Index: 1.5341 (estimate)
• Storage Temp.: Desiccate at +4°C
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly)
• PKA: 10.27±0.70(Predicted)
• Merck: 14,7755
• CAS DataBase Reference: Probucol(CAS DataBase Reference)
• NIST Chemistry Reference: Probucol(23288-49-5)
• EPA Substance Registry System: Probucol(23288-49-5)

Safety Data

• WGK Germany: 2
• RTECS: AL3705000
• Hazardous Substances Data: 23288-49-5(Hazardous Substances Data)

Usage

Description

Probucol, also known as 4,4'-[(1-methylethylidene)bis(thio)]bis[2,6-bis(1,1-dimethylethyl)phenol], is a bis-phenol antioxidant with anti-hyperlipidemic activity. Initially developed for the treatment of coronary artery disease, it has a high lipophilic character due to its molecular structure, which features two tertiary butylphenol groups linked by a dithiopropylidene bridge. This chemical agent was developed for the plastics and rubber industry in the 1960s and has strong antioxidant properties. In humans, it causes a reduction of both liver and serum cholesterol levels without altering plasma triglycerides. It is effective at reducing levels of LDL and, to a lesser extent, HDL, through a unique mechanism that is still not clearly delineated.

Uses

Used in Pharmaceutical Industry:
Probucol is used as an antihyperlipidemic agent for reducing high levels of cholesterol in blood. It accelerates the fractional rate of low-density (LDL) catabolism, which is the final pathway of cholesterol elimination inside the body. It may also inhibit the early stage of cholesterol biosynthesis and dietary cholesterol absorption.
Used in Treatment of Hyperlipoproteinemias:
Probucol is used as an antilipemic and anti-hyperlipoproteinemic agent for treating hyperlipoproteinemias characterized by elevated LDL levels. It reduces LDL and, to a lesser extent, HDL levels through a unique mechanism that is still not clearly delineated. The reduction of HDL may be caused by the ability of probucol to inhibit the synthesis of apoprotein A-1, a major protein component of HDL.
Used in Antioxidant and Anti-inflammatory Applications:
Probucol is used as an antioxidant, anti-inflammatory, and hypocholesterolemic agent which inhibits atherogenesis in murine models. Its strong antioxidant properties make it a promising candidate for various pharmaceutical applications.
Chemical Properties:
Probucol is a white solid with the brand name Lorelco (Sanofi Aventis). It is a dithioketal that is propane-2,2-dithiol in which the hydrogens attached to both sulfur atoms are replaced by 3,5-di-tert-butyl-4-hydroxyphenyl groups.

References

https://www.drugbank.ca/drugs/DB01599 https://pubchem.ncbi.nlm.nih.gov/compound/probucol#section=Top https://en.wikipedia.org/wiki/Probucol

Biological Functions

Probucol (Lorelco) is a hypocholesterolemic drug with few side effects that modestly (15–30%) decreases elevated plasma LDL cholesterol levels. The marginal LDL-lowering action plus reports that it can lower HDL cholesterol resulted in its discontinuation as a hypocholesterolemic drug. However, it still may reduce the risk of CHD because it is a powerful antioxidant. The oxidation hypothesis of atherosclerosis states that oxidation of lipids in LDL is required for LDL uptake by macrophages and smooth muscle cells in the intima of arteries, leading to their transformation to foam cells, an early event in atherogenesis. A recent clinical trial reported that use of probucol decreased the rate of restenosis of coronary arteries by 50% in patients who underwent angioplasty. Fluvastatin also has potent antioxidant properties that may contribute to its antiatherosclerotic effects.These findings suggest that reducing high plasma lipids may not be the only approach to retarding the progression of atherosclerosis and decreasing the risk of coronary heart disease.

Biological Activity

Antioxidant, anti-inflammatory and hypocholesterolemic agent. Inhibits atherogenesis in genetically hypercholesterolemic rabbits (Watanabe) and attenuates ischemia/reperfusion-induced cardiomyocyte apoptosis.

Mechanism of action

Probucol reduces the overall level of cholesterol—primarily low-density lipoproteins— without having an effect on triglycerides and very low-density lipoproteins. It has been suggested that it inhibits synthesis of cholesterol itself and increases removal of bile salts. Upon using this drug, a fraction of low-density proteins is reduced; however, even more significant is the reduction of high-density proteins. From the epidemiological point of view, this is dangerous, because lowering the concentration of high-density proteins means less cholesterol is removed from tissues. However, in any case, probucol lowers the level of cholesterol in the plasma by 10–15%. Moreover, it has been shown that probucol facilitates reduction of necrotic zones in myocardial ischemia.

Pharmacology

Being a lipophilic compound, it is easily distributed into fatty tissue and, as a result, approximately 20% of its maximum concentration in the blood is still maintained for 6 months.

Synthesis

Probucol, bis(3,5-tert-butyl-4-hydroxyphenyl)mercaptol acetone (20.2.6), is synthesized by thioketalizing acetone with 2,6-di-tert-butyl-4-mercaptophenol in the presence of hydrogen chloride.

InChI:InChI=1/C31H48O2S2/c1-27(2,3)21-15-19(16-22(25(21)32)28(4,5)6)34-31(13,14)35-20-17-23(29(7,8)9)26(33)24(18-20)30(10,11)12/h15-18,32-33H,1-14H3

Upstream product

• 950-59-4 4-hydroxy-3,5-di-tert-butylthiophenol 
• 67-64-1 acetone 

Downstream Products

• 216168-57-9 {2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxyphenylsulfanyl)-1-methylethylsulfanyl]phenoxy}acetic acid ethyl ester 
• 2455-14-3 3,5,3',5'-tetra-tert-butyl-4,4'-diphenoquinone 
• 216168-29-5 2-Propenoic acid, 4-[4-[[-1-[[-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyl ester 
• 216167-82-7 probucol monosuccinate 
• 108-95-2 phenol 
• 110-99-6 2,2'-oxybis-acetic acid 
• 110-94-1 1,5-pentanedioic acid 
• 110-15-6 succinic acid 
• 216167-95-2 butanoic acid, 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)4-hydroxyphenyl]thio]-1-methylethyl]-thio]-2,6-bis(1,1-dimethylethyl)phenoxy] 
• 216168-59-1 methyl 4-[4-[[1-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]-1-methylethyl]thio]-2,6-bis(1,1-dimethylethyl)phenoxy]butyrate 
• 216168-61-5 2-(2-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-acetylamino)-pentanedioic acid diethyl ester 

Relevant articles and documents

METHODS FOR PRODUCING 2,6-DI-TERT-BUTYL-4-MERCAPTOPHENOL AND 4,4'-ISOPROPYLIDENEDITHIOBIS[2,6-DI-TERT-BUTYLPHENOL]

The present invention provides a method for producing 2,6-di-tert-butyl-4-mercaptophenol containing reducing bis(3,5-di-tert-butyl-4-hydroxyphenyl) polysulfide with zinc in a mixed solvent of toluene and n-butanol, and provides a method for producing 4,4'-isopropylidenedithiobis[2,6-di-tert-butylphenol] using the above-mentioned method.

Carotenoid ester analogs or derivatives for controlling C-reactive protein levels

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