500-38-9

Basic information

• Product Name: Nordihydroguaiaretic acid
• Synonyms: 4,4’-(2,3-dimethyltetramethylene)di-pyrocatecho;beta,gamma-Dimethyl-alpha,delta-bis(3,4-dihydroxyphenyl)butane;Butane, 1,4-bis(3,4-dihydroxyphenyl)-2,3-dimethyl-;dihydro-dinorguaiareticaci;Dihydronorguaiaretic acid;dihydro-norguaiareticaci;dihydronorguaiareticacid;Dinorguaiaretic acid, dihydro-
• CAS NO: 500-38-9
• Molecular Formula: C₁₈H₂₂O₄
• Molecular Weight: 302.36
• EINECS: 207-903-0
• Product Categories: Aromatic Phenols;Aromatics;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 500-38-9.mol
• Article Data: 3

Chemical Properties

• Melting Point: 182-187 °C
• Boiling Point: 363.4°C (rough estimate)
• Flash Point: 247.8 °C
• Appearance: White to off-white/Powder
• Density: 1.0772 (rough estimate)
• Vapor Pressure: 1.06E-11mmHg at 25°C
• Refractive Index: 1.4230 (estimate)
• Storage Temp.: Freezer (-20°C)
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.56±0.10(Predicted)
• Water Solubility: slightly soluble
• Stability: Stable. Incompatible with oxidizing agents.
• Merck: 14,6693
• BRN: 2056825
• CAS DataBase Reference: Nordihydroguaiaretic acid(CAS DataBase Reference)
• NIST Chemistry Reference: Nordihydroguaiaretic acid(500-38-9)
• EPA Substance Registry System: Nordihydroguaiaretic acid(500-38-9)

Safety Data

• Hazard Codes: Xn
• Statements: 22-36/37/38
• Safety Statements: 26-36/37-37/39-24/25-22
• WGK Germany: 3
• RTECS: UX1750000
• Hazardous Substances Data: 500-38-9(Hazardous Substances Data)

Usage

Description

Nordihydroguaiaretic acid (NDGA) is a grayish-white crystalline compound that was widely used as an antioxidant in animal fats in the 1950s and 1960s. It possesses phenolic properties similar to gallates, including their advantages and disadvantages. Besides the isolation of natural material (resinous exudate of creosote bush), NDGA has also been chemically synthesized. As the result of unfavorable toxicological findings, NDGA is prohibited from use in the US. More specifically, NDGA is a potent lipoxygenase inhibitor which interferes with arachidonic acid metabolism. The compound also inhibits formyltetrahydrofolate synthetase, carbox- ylesterase,and,to a lesser extent, cyclooxygenase.

Chemical Properties

Nordihydroguaiaretic acid is a white to light yellow crystalline powder. Melting range 183～185℃. Insoluble in water. Slightly soluble in hot water. Soluble in alcohol, ether, glycerol, propylene glycol. About 0.5% is dissolved in oil. It has good antioxidant effect and is also effective against mildew. It has a synergistic effect when used in combination with citric acid and ascorbic acid.

Uses

Nordihydroguaiaretic acid is used in the treatment of multiple diseases, including cardiovascular diseases, neurological disorders and cancers. It is also used as an antioxidant.

Definition

ChEBI: Nordihydroguaiaretic acid is a tetrol that is butane which is substituted at positions 2 and 3 by 3,4-dihydroxybenzyl groups. Masoprocol, the meso-form found in the leaves of the creosote bush (Larrea divaricata), is a potent lipoxygenase inhibitor. It has a role as an antioxidant, a plant metabolite, a ferroptosis inhibitor and a geroprotector. It is a member of catechols, a tetrol and a lignan.

Application

Nordihydroguaiaretic acid (NDGA) is an antioxidant that has poor solubility and shows evidence of discoloration in the presence of metal salts. It is used to a limited extent to retard rancidity. NDGA is a broad bean lipoxygenase inhibitor that polyphenol-bearing o-dihydroxy (catechol) structure. The oxidation product from Resveratrol (R150000) showed a high inhibitory activity, w hereas Resveratrol itself had no activity and its oxidation efficiency was low.

Preparation

Nordihydroguaiaretic acid is obtained by hydrodemethylation of dimethyl ether of guaiacolinic acid, a component of guaiac resin. It is also produced from desert plant, creosote bush (Larrea divaricata Cav. Or Corillea tridentate), which can be widely found in the border zone of southern of USA and northern of Mexico.

benefits

Nordihydroguaiaretic acid is a kind of antioxidant compound presented in the creosoten bush. It is a potent in vitro scavenger of many kind of oxidants such as peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid. Studies have shown that it has various physiological effects. It can also protect hippocampal neurons against amyloid β-peptide toxicity, and attenuates free radical and calcium accumulation. Rat study has shown that it can block the synaptic component of long-term potentiation and the associated increases in release of glutamate and arachidonate. Two most exciting results are that: (1) it has the potential to increase lifespan of animals; (2) it can suppress growth of breast cancer cells through inhibiting the IGF-1 and c-erbB2/HER/NEU receptors.

General Description

Nordihydroguaiaretic acid (NDGA) is used as an powerful antioxidant and potent scavenger of reactive oxygen species (ROS). NDGA is a phenolic lignan obtained from Larrea tridentata, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging.

Hazard

Use in foods prohibited by FDA.

Biochem/physiol Actions

Lipoxygenase inhibitor; polyphenol-bearing o-dihydroxy (catechol) structure.

Safety Profile

Moderately toxic by intraperitoneal route. An antioxidant food additive. When heated to decomposition it emits acrid smoke and irritating fumes.

Purification Methods

Crystallise the acid from dilute acetic acid. [Beilstein 6 IV 7771.]

References

Floriano-Sánchez, E, et al. "Nordihydroguaiaretic acid is a potent in vitro scavenger of peroxynitrite, singlet oxygen, hydroxyl radical, superoxide anion and hypochlorous acid and prevents in vivo ozone-induced tyrosine nitration in lungs." Free Radical Research 40.5(2006):523.Goodman, Yadong, et al. "Nordihydroguaiaretic acid protects hippocampal neurons against amyloid β-peptide toxicity, and attenuates free radical and calcium accumulation." Brain Research 654.1(1994):171.Lynch, M. A., M. L. Errington, and T. V. Bliss. "Nordihydroguaiaretic acid blocks the synaptic component of long-term potentiation and the associated increases in release of glutamate and arachidonate: an in vivo study in the dentate gyrus of the rat." Neuroscience 30.3(1989):693-701.Strong, Randy, et al. "Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice." Aging Cell 7.5(2008):641-650.Youngren, Jack F., et al. "Nordihydroguaiaretic Acid (NDGA) Inhibits the IGF-1 and c-erbB2/HER2/neu Receptors and Suppresses Growth in Breast Cancer Cells." Breast Cancer Research & Treatment 94.1(2005):37-46.

InChI:InChI=1/C18H22O4/c1-11(7-13-3-5-15(19)17(21)9-13)12(2)8-14-4-6-16(20)18(22)10-14/h3-6,9-12,19-22H,7-8H2,1-2H3/t11-,12-/m1/s1

Synthetic route

1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane (5701-82-6) → nordihydroguaiaretic acid (500-38-9)

Conditions	Yield
With hydrogen bromide In water at 126℃; for 10h; Reagent/catalyst; Inert atmosphere;	91.26%

meso-2.3-bis-<3.4-carbonyldioxy-benzyl>-butane → nordihydroguaiaretic acid (500-38-9)

Conditions	Yield
With hydrogenchloride

L-phenylalanine (63-91-2) → para-coumaric acid (7400-08-0) + nordihydroguaiaretic acid (500-38-9)

Conditions	Yield
With Larrea divaricata Cav. callus cells In ethanol Enzymatic reaction;

3,4-dimethoxyphenylacetone (776-99-8) → nordihydroguaiaretic acid (500-38-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: titanium tetrachloride; zinc / tetrahydrofuran / 5 h / Inert atmosphere; Reflux 1.2: 2 h / 20 °C / Inert atmosphere 2.1: trifluoroacetic acid; HSiPh3 / dichloromethane / 48.5 h / 20 °C / Inert atmosphere 3.1: hydrogen bromide / water / 10 h / 126 °C / Inert atmosphere View Scheme

bis(phenyl) carbonate (102-09-0) + nordihydroguaiaretic acid (500-38-9) → 5,5'-(2,3-dimethylbutane-1,4-diyl)bis(benzo[d][1,3]dioxol-2-one)

Conditions	Yield
With triethylamine In diethyl ether at 20℃; for 48h;	90.8%

2,3-dibromopropionic acid ethyl ester (3674-13-3) + nordihydroguaiaretic acid (500-38-9) → C28H34O8

Conditions	Yield
With potassium carbonate In acetone for 18h; Reflux;	85.5%

dichloromethane (75-09-2) + nordihydroguaiaretic acid (500-38-9) → 5,5'-(2,3-dimethylbutane-1,4-diyl)bis(benzo[d][1,3]dioxole) (77150-81-3)

Conditions	Yield
With sodium hydroxide In dimethyl sulfoxide at 120℃;	73%

Triethyl orthoacetate (78-39-7) + nordihydroguaiaretic acid (500-38-9) → 5,5'-(2,3-dimethylbutane-1,4-diyl)bis(2-ethoxy-2-methylbenzo[d][1,3]dioxole)

Conditions	Yield
With Amberlyst-15 In toluene at 100℃;	69.2%

L-Cysteine (52-90-4) + nordihydroguaiaretic acid (500-38-9) → 5′-S-cysteinylnordihydroguaiaretic acid

Conditions	Yield
With peroxidase from horseradish; dihydrogen peroxide In methanol; water at 25℃; Enzymatic reaction;	20%

diazomethane (186581-53-3, 908094-01-9) + nordihydroguaiaretic acid (500-38-9) → 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane (5701-82-6)

Conditions	Yield
In diethyl ether for 5h;	2.4%

nordihydroguaiaretic acid (500-38-9) → benzene-1,2-diol (120-80-9)

Conditions	Yield
at 290 - 320℃; under 3 Torr;

nordihydroguaiaretic acid (500-38-9) → poly(nordihydroguaiaretic acid)

Conditions	Yield
In phosphate buffer pH=7.4; Product distribution; Kinetics; Further Variations:; Reagents; Polymerization; oxidative electropolymerization; Electrolysis;

methyl iodide (74-88-4) + nordihydroguaiaretic acid (500-38-9) → 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane (5701-82-6)

Conditions	Yield
With potassium carbonate In acetone for 10h; Heating;

dimethylaminoacetic acid (1118-68-9) + nordihydroguaiaretic acid (500-38-9) → meso-1,4-bis[(3,4-dimethylaminoacetoxy)phenyl]-(2R,3S)-dimethylbutane hydrochloride salt

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 24h;

nordihydroguaiaretic acid (500-38-9) → C18H18Cl6O4P2 (1439194-69-0)

Conditions	Yield
Stage #1: nordihydroguaiaretic acid With chloro-trimethyl-silane; triethylamine Stage #2: With phosphorus trichloride Stage #3: With chlorine

nordihydroguaiaretic acid (500-38-9) → C24H24Cl2O6

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / acetone / 18 h / Reflux 2: sodium hydroxide / methanol; water / 18 h 3: thionyl chloride / Reflux View Scheme

nordihydroguaiaretic acid (500-38-9) → N-(2-hydroxyethyl)-7-(4-(2-((2-hydroxyethyl)carbamoyl)-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-2,3-dimethylbutyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate / acetone / 18 h / Reflux 2: sodium hydroxide / methanol; water / 18 h 3: thionyl chloride / Reflux 4: dichloromethane / 0 - 20 °C View Scheme

Upstream product

• 776-99-8 3,4-dimethoxyphenylacetone 
• 5701-82-6 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane 
• 63-91-2 L-phenylalanine 

Downstream Products

• 120-80-9 benzene-1,2-diol 
• 5701-82-6 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane 

Relevant articles and documents

Novel synthetic method of nordihydroguaiaretic acid (NDGA)

Nordihydroguaiaretic acid has wide physiological activity and pharmacological activity. The invention discloses a novel synthetic method of nordihydroguaiaretic acid, wherein the method comprises thefollowing steps: carrying out reductive coupling reaction on veratone serving as a raw material under the action of a catalyst to obtain pinacol; reducing pinacol by trialkylsilane or triarylsilane under the catalysis of protonic acid or Lewis acid to generate 1,4-bis(3,4-dimethoxyphenyl)-2,3-dimethylbutane; and finally, under the action of haloid acid or Lewis acid, breaking ether bonds, and synthesizing nordihydroguaiaretic acid. The structure of the compound is characterized by 1H-NMR. Raw materials and reagents used in the method are easy to obtain, the reaction route is short, the reaction conditions are mild, the yield is high, the cost is low, and a simple and convenient path is opened up for industrial synthesis of nordihydroguaiaretic acid.

Diarylalkanes as potent inhibitors of binuclear enzymes

The present invention implements a strategy that combines an enzyme inhibition assay with a chemical dereplication process to identify active plant extracts and the particular compounds—diarylalkanes and/or diarylalkanols within those extracts that specifically inhibit binuclear enzyme function. Included in the present invention are compositions of matter comprised of one or more of diarylalkanes and/or diarylalkanols, which inhibit the activity of binuclear enzymes, particularly tyrosinase and which prevent melanin overproduction. The present invention also provides a method for inhibiting the activity of a binuclear enzyme, particularly tyrosinase and a method for preventing and treating diseases and conditions related to binuclear enzyme function. The present invention further includes a method for preventing and treating melanin overproduction and diseases and conditions of the skin related thereto. The method for preventing and treating diseases and conditions related to binuclear enzyme function and melanin overproduction is comprised of administering to a host in need thereof an effective amount of a composition comprising one or more diarylalkanes and/or diarylalkanols synthesized and/or isolated from one or more plants together with a pharmaceutically acceptable carrier.