302-79-4 Usage
Uses
Used in Pharmaceutical Industry:
Tretinoin is used as a keratolytic agent for the treatment of various skin conditions, including acne, psoriasis, ichthyosis, follicular keratosis, lichen planus, verrucous epidermal nevus, impetigo, vitiligo, lichen psoriasis, and pityriasis alba. It promotes epithelial cell proliferation and turnover, inhibits the proliferation and differentiation of keratinocytes, and helps normalize hyperkeratosis.
Used in Antineoplastic Applications:
Tretinoin is used as an antineoplastic agent, particularly in the treatment of acute promyelocytic leukemia (APL). It induces cell differentiation and has been shown to result in the destruction of the PML-RAR fusion protein, which is involved in the development of APL.
Used in Antiacne Applications:
Tretinoin is used as an antiacne agent, helping to treat abnormal types of acne, fish phosphorus disease, and abnormal psoriasis. It alters collagen synthesis, increases dermal hyaluronic acid levels, and stimulates fibroblast growth and the extracellular matrix, making it effective in treating acne and improving the visible signs of aging.
Used in Antipruritic Applications:
Tretinoin is used as an antipruritic agent, helping to alleviate itching associated with various skin conditions.
Used in Cosmetic Industry:
Tretinoin is used in the cosmetic industry for its anti-aging effects. It is often used for treating the visible signs of aging, although the results can take approximately 6 months to become visible. However, it is associated with several adverse effects, including irritation, photosensitivity, skin dryness, redness, and peeling. It should not be used while pregnant.
Used in Research Applications:
Tretinoin is used as a physiological metabolite of vitamin A, affecting gene expression via nuclear retinoic acid receptors (RAR) and mediating cellular growth and differentiation. It is also used in research to study its effects on various biological processes and its potential applications in medicine.
Brand names for Tretinoin include A-acido, Acid a vit, Acnavit, Acnefug, Acretin, Airoderm, Aknebont, Dermoclar, Retin-A, and many others.
Dermatology drugs
Retinoic acid（Tretinoin） is commonly used in dermatology drugs, which is the department of vitamin A (Victoria methanol) metabolic intermediates.It mainly affects the growth of bones and epithelial metabolism, can promote epithelial cell proliferation and updates, and can inhibit the proliferation and differentiation of keratinocytes, so hyperkeratosis can be back to normal. Therefore many complete or incomplete keratosis, hyperkeratosis of diseases have a certain therapeutic effect, treat a variety of skin diseases. The use of the drug can penetrate topical skin quickly, enable significantly increased epithelial cell turnover. This class of drugs has strong and rapid inhibition on the secretion of the sebaceous glands, can reduce sebum secretion. In addition, the product also has anti-tumor, promote wound healing and anti-inflammatory effects.
Clinical application
Retinoic acid is mainly used in the treatment of psoriasis, ichthyosis, follicular keratosis, acne, lichen planus, verrucous epidermal nevus, impetigo, vitiligo, lichen psoriasis, the face of pityriasis alba, etc. In addition, the drugs also have some preventive effect on skin cancer.
Tretinoin Cream
Physicochemical property
Retinoic acid is a yellow needle crystal, with a similar smell of vitamin acetate. Soluble in methanol, ethanol, acetone, chloroform, dichloromethane , also in vegetable oil and fatty. In case of light, it is thermal instability, suck up moisture in the air, polymerization and metamorphism in water. The melting point of all trans-vitamin A acid is 182~180°C, the melting range of which is mixed with a small amount of isomers is 170~190°C.
Tretinoin structure
Pharmacological action
Retinoic acid can induce epidermal hyperplasia, and improve the granular layer and the cell layer thickness.It can influence the silk protein process and the formation of cross-linked film and promote the differentiation of epidermal granular layer cells in the late stage of the differentiation of the epidermal cells by affecting K10, K1 keratin solution. This product can significantly inhibit the formation of experimental acne, prevent and eliminate acne lesions. Tretinoin also affect melanocyte cell melanogenesis , it has more than a number of functional points, having inhibitory effect on the activity of Tyrosine hydroxylase, dopa oxidase and two hydroxyindole oxidase three catalyzing enzyme, so as to reduce the formation of melanin, reduce skin pigmentation. It has no effect on the normal black prime cellular tyrosinase activity and black pigment composition.
Pharmacodynamics
Tretinoin can increase the cell nucleus division and epidermal cell turnover, form of the stratum corneum cell adhesion, and easy to fall off. It can remove the existing acne, while inhibiting the formation of new acne, hair follicle epithelial replacement can prevent the blockage of the plug. The synthesis of keratin is also inhibited, which can affect the metabolism of epithelial cells. It has the effect of promoting the proliferation and differentiation of epithelial cells, and the dissolution of keratinocytes.
Pharmacokinetics
External use has a small amount of skin absorption, large area of application of the increase in absorption. About 5% of the amount of external use urine. This product is absorbed well, the blood can reach the concentration peak after 3 hours, blood concentration can reach 0.3~0.5mg/ml, after oral administration of 1 mg/kg. After oral absorption, it is widely combination with plasma protein and has half-life of 0.7 h in a mean elimination. After a single oral dose of 40mg, blood drug concentration can be up to the source metabolic level in 7~12 hours. Multiple oral administration has not seen in vivo accumulation, but the blood concentration of the drug is significantly decreased, which may be due to the induction of cytochrome P450 enzymes, and the elimination of the rate of increase and bioavailability. It mainly used in the liver metabolism, which is metabolites of glucose acid esters. 60% of metabolites is by renal excretion, and can also be excreted by bile but metabolite half-life is longer.
Pharmacokinetics
A small amount is absorbed by the skin through external use, and absorption increases as application area increases. Approximately 5% of the externally applied amount is excreted through urine. This product is well-absorbed when taken orally and reaches peak blood concentration in 3 hours. With an oral dosage of 1mg/kg, blood concentration can reach 0.3-0.5 mg/ml. After oral absorption, it will bind universally with serum protein, and its average clearing half-life is 0.7 hours. After a single 40mg dose, blood concentration reaches its endogenous metabolism level in about 7-12 hours. Multiple oral doses do not appear to accumulate in the body, but blood concentration will noticeably decrease, possibly due to the induction of cytochrome P450, thus causing the clearing rate to increase and bioavailability to decrease. It is mainly metabolized in the liver, and its metabolite is esterified glucuronic acid. 60% of the drug is excreted by the kidneys, it can also be excreted through bile, and its metabolite’s half-life is longer than that of the drug itself.
Vitamin A acid medicine
Vitamin A acid medicine is a kind of natural or synthetic existence with vitamin A activity of retinol (retinol) derivatives. The drug discovery is regarded as a new milepost for treatment of skin diseases and cosmetic pharmacology. In the last 20 years, the application of the dimension A acid has made great progress in the treatment of many skin diseases. So far, there have been 2500 retinoic acid derivatives. According to its development process and chemical structure, they can be divided into three generations: the first generation is class of non aromatic retinoid, tretinoin and isotretinoin as the representative. The second generation is class of single aromatic A acids, etretinate and acitretin as the representative; the third generation is class of aromatic dimensional A acid, aromatic methyl ethyl acetylene, adapalene and vitamin A acid ethyl ester as the represented.
use of of vitamin A in skin diseases
The indications
Used in the treatment of acne vulgaris, especially the blackhead acne lesions, senile, fluorescent or drug skin atrophy, ichthyosis and various abnormal keratinization and pigment excessive calm skin disease, and psoriasis.
Usage dosage
(1) ointment: use 0.1% ointment for the other skin lesions and 0.05% ointment for acne skin lesions in the topical application. Clean the skin with warm water after one time every night.
(2) gel: apply to the affected area. At the beginning of treatment , it can be taken one time every two days or every three days. Afterwards smear one time every night.
Adverse reaction
This product may cause skin irritation symptoms such as burning, erythema, swelling, desquamation, crusting, pigment increase or decrease, may make the skin lesions more obvious, but also showed that the drug is working, not aggravated illness. Most of the skin can be adapted and tolerated, the phenomenon can be gradually disappeared. If irritation persists or increased, you can take intermittent or suspended medication.
Precautions
(1) This drug is contraindicated in pregnant women and patients with the allergic to the Tretinoin, the A derivative of vitamin A, acute or subacute dermatitis, eczema, skin diseases.
(2) Allergic caution.
(3) Women should stop breastfeeding during the period of the nursing period. Women of childbearing age are prohibited during the period of pregnancy .Children with caution.
(4) The product should avoid contacting with eyes and other mucous membranes (e.g., mouth, nose, etc.). Do not use in skin of wrinkling location and skin ulceration.
(5) The site of using medicine, appearing the things such as burning, itching, redness, etc. should discontinue medication, and the local is washed clearly. Consult the doctor if necessary.
(6) For the treatment of acne, the first few weeks ache can be temporarily intensified, but should continue to treat more than 6 weeks to reach the maximum effect.
(7) The product should not be used in large areas, the daily dosage should not exceed 20g.
(8) During the course of medication, do not use other drugs ,which can cause irritation and damage to skin, cosmetics and cleaning agents, so as not to aggravate the skin reaction, resulting in increase in drug absorption and cause systemic adverse reactions.
(9) The sun can accelerate Tretinoin decomposition and stimulate heavier to the skin. Animal experiments suggest that Tretinoin can enhance the ability of ultraviolet radiation, so the product is most appropriate in the evening and bedtime application, the treatment process should avoid the sun, or the use of shading measures.
Drug interaction
(1)Retinoic acid combining with light sensitive drugs can increase the risk of photosensitiveness.
(2)Retinoic acid combining with soap and detergents, containing keratolytic agents (such as peroxy benzoic acid, Resorcinol, salicylic acid, sulfur,etc), ethanol preparation, isotretinoin can aggravate irritation or dryness to skin, and therefore must be used with caution.
(3) Retinoic acid combining with sago cimetidine, cyclosporine and diltiazem, verapamil and ketoconazole, can cause an increase in the blood concentration of the drug, and may lead to retinoic acid poisoning.
(4 Retinoic acid combining with pentobarbital, rifampicin, phenobarbital, can cause the blood concentration of the product decreasing.
(5) The product will affect the liver cytochrome P450 enzyme system, resulting in changes in blood concentrations of the drug.
(6)Taking drugs oryzanol, vitamin B1, vitamin B6 with Tretinoin, can make headache relieved or disappeared, because of adverse reactions of the drug.
There are Informations on Common tretinoin in the Department of Dermatology,incluing the pharmacological effects , pharmacokinetics, pharmacodynamics, indications, drug interactions, and adverse reaction of the drug, these were edited by Yuri Huang in the chemcialbook (2015-09-24).
Indications and Usage
Retinoic acid is a commonly used dermatological drug and an intermediate product in bodily vitamin A (dimethyl alcohol) metabolism. It has a similar odor to that of vitamin A acetate. It is easily soluble in methanol, ethanol, acetone, chloroform, dichloromethane, and it is also soluble in vegetable oil and fats. It is instable when in contact with light and heat, hygroscopic in air, and polymerizes and metamorphosizes when in contact with water.
Retinoic acid also anti-tumor, wound-healing, and infection-resisting effects. It is mainly used clinically to treat psoriasis, hair follicle keratosis, acne, lichen planus, verrucous epidermis nevus, ureophora, vitiligo, pityriasis rosea, and facial pityriasis simplex, especially blackhead skin lesions, and senile, sun-induced, or drug induced skin atrophy, as well as various keratosis abnormalities and hyperpigmentation diseases. In addition, it also has certain preventative effects against skin cancer. Retinoic acid can significantly inhibit experimental acne breakouts.
Mechanisms of Action
Retinoic acid mainly affects bone growth and epithelium metabolism, it can promote epithelium cell growth and renewal, and it can inhibit keratinocyte growth and differentiation to correct hyperkeratosis. Thus, it has certain curative effects on diseases related to keratinization, hypokeratinization and hyperkeratinization. A localized application can penetrate the skin very quickly and cause significant growth in epithelial cells. Retinoic acid has a strong and rapid inhibiting effect on sebaceous glands and can reduce sebum secretion. Retinoic acid promotes epidermal growth, thickens the stratum granulosum and stratum spinosum, and affects K1 and K10 keratinysis in late stage epidermal cell differentiation to influence the siloxin to silymeric protein process and cross-linked coating formation, thus promoting epidermal granulosa cells to differentiate towards the cuticle layer. It regulates follicular sebaceous gland epithelium keratinization abnormalities to remove keratin plugs, thus being able to prevent and remove acne lesions, and follicular epithelial renewal can also prevent keratin plugs and acne formation. In addition, retinoic acid can also affect melanogenesis of melanocytes with a multi-site effect, and it can inhibit the activity of tyrosine hydroxylase, dopa oxidase, dihydroxyl indole oxidase, and other type-three catalytic enzymes, thus lowering the formation of melanin and reducing hyperpigmentation. It has not impact on normal human melanocyte tyrosinase activity and melanin content.
Drug Interactions
Combined use with light-sensitive drugs may increase the risk of light sensitivity.
Use with caution when combined with soap and other detergents, preparations containing keratolytic (such as benzoyl peroxide, thalidomide, salicylic acid, and sulfur), preparations containing ethanol, or isotretinoin, as this may worsen skin irritation and dryness.
Combined use with cimetidine, cyclosporine, diltiazem, verapamil and ketoconazole may increase the blood concentration of this drug and lead to retinoic acid poisoning.
Combined use with pentobarbital, phenobarbital and rifampicin may decrease the blood concentration of this drug.
This drug will impact the hepatic cytochrome P450 enzyme system and change the blood concentration of this drug.
Taking oryzanol, vitamin B1 or vitamin B6 while also taking this drug may alleviate or eliminate adverse effects of this drug, including headaches.
Adverse reactions
May cause skin irritations such as a burning sensation, erythema, swelling, desquamation, scabbing, or change in pigmentation. May cause skin lesions to become more obvious, but this means that the drug is taking effect, and not that the condition is worsening. Mostly tolerated or tolerable on the skin, and irritation may subside gradually. If irritation continues or worsens, use periodically or cease use.
Warnings and Precautions
Patients who are allergic to this drug or vitamin A derivatives, have acute or subacute dermatitis, have eczema or related skin diseases, and pregnant women should not use this drug.
Use with caution if susceptible to allergies.
Breastfeeding women should stop breastfeeding when using this drug, and women of childbearing age should not get pregnant when using this drug. Children should use with caution.
Keep drug out of eyes and other mucosa (such as mouth and nose). Not suitable or skin folds and skin ulcerations.
If the applied area experiences burning sensation, itching, or redness and swelling, stop use immediately, clean the applied area, and consult a physician if necessary.
This drug is used to treat acne, and a couple weeks of use can prevent worsening, while continued use for over 6 weeks will have the best curative effect.
This drug is not suitable use in large areas, and daily dosage should not exceed 20g.
While using this drug, do not use any drugs, cosmetics, or cleansers that may irritate and damage the skin to prevent worsened skin reactions and adverse effect caused by increased drug absorption.
Sunlight can increase retinoic acid’s irritation to skin and break down retinoic acid. Animal studies showed that retinoic acid can increase the carcinogenic ability of ultraviolet rays, so this drug is best used at night and before sleep. Avoid direct sunlight during treatment, or protect treated areas from sunlight.
Originator
Aberel,McNeil,US,1973
Indications
Topical tretinoin (Retin-A, Renova, Avita), like isotretinoin,
alters keratinization in the acroinfundibulum.
In addition, it reverses certain premalignant and other
histological changes associated with the photoaging
changes that accompany chronic exposure to ultraviolet
radiation. Topically applied tretinoin is indicated in
comedogenic and papulopustular acne vulgaris, and its
mild exfoliative effects make it sometimes useful in molluscum
contagiosum, flat warts, and some ichthyotic disorders.
It is often prescribed to lessen the clinical signs of
photoaging (wrinkling and hyperpigmented macules).
Manufacturing Process
100 parts of beta-ionol are dissolved in 200 parts of dimethylforrnamide and
after the addition of 165 parts of triphenylphosphine hydrobromide, stirred for 7 hours at room temperature. Then 70 parts of 4-methyl-1-al-hexadiene-
(2,4)-acid-(6) (melting point 177°C, white needles from water) are added to
the now clear solution. 150 parts of isopropanol are added and the whole
cooled to -30°C. Into this solution, while stirring vigorously, 190 parts by
volume of a 30% solution of sodium methylate in methanol are allowed to
flow in. A vigorous exothermic reaction takes place and the temperature in the
interior of the flask rises to +5°C. It is stirred for another 5 minutes and
neutralized with 10% of sulfuric acid (until acid to Congo).
After stirring for 2 hours at room temperature, the mass of vitamin A acid has
crystallized out. It is sharply filtered off by suction and washed with a little
ice-cold isopropanol. From the filtrate, a further small amount of mainly all
trans vitamin A acid crystallizes out upon the addition of water. The filter cake
is suspended in 600 parts of water and stirred for 4 hours at room
temperature; it is filtered by suction and the product washed with water. It is
dried in vacuo at 40° to 50°C and 115 parts of vitamin A acid are obtained.
The melting point lies between 146° and 159°C.
The mixture of the all trans and mainly 9,10-cis vitamin A acid may be
separated by fractional crystallization from ethanol. All trans vitamin A acid
has a melting point of 180° to 182°C and 9,10-cis vitamin A acid, which
crystallized in the form of pale yellow fine needles collected into clusters, has
a melting point of 189° to 190°C.
World Health Organization (WHO)
Tretinoin, a retinol derivative, was introduced in 1973 exclusively
for the topical treatment of severe acne. Preparations of tretinoin are indicated for
topical use only since oral administration has been associated with risk of toxicity
from hypervitaminosis-A and subsequently of teratogenicity.
Air & Water Reactions
Tretinoin may be sensitive to prolonged exposure to air. Insoluble in water.
Reactivity Profile
Tretinoin may discolor on exposure to light. Tretinoin is extremely sensitive to exposure to light and, therefore, Tretinoin should be fully protected from light during all handling. Solutions are unstable in the presence of strong oxidizers. Tretinoin is incompatible with strong oxidizing agents. .
Fire Hazard
Flash point data for Tretinoin are not available; however, Tretinoin is probably combustible.
Biological Activity
Endogenous agonist for retinoic acid receptors. Also positively modulates PPAR δ receptors (K d = 17 nM). Promotes differentiation of embryonic stem cells (ESCs) into adipocytes, neurons and glia in vitro .
Biochem/physiol Actions
all?trans?Retinoic acid (ATRA) is a ligand for both the retinoic acid receptor (RAR) and the retinoid X receptor (RXR). The bound RAR and RXR act as transcription factors that regulate the growth and differentiation of both normal and malignant cells. Cytochromes P450 (CYPs) catalyze the 4-hydroxylation of ATRA. Retinoic acid primes embryonic stem cells to become neurons.
Clinical Use
The major toxic effect of tretinoin is erythema and
irritation of the skin to which it is applied, especially if
the skin is moist.This toxicity often decreases with continued
therapy.
Safety Profile
Poison by ingestion,
intraperitoneal, subcutaneous, and
intravenous routes. Experimental
reproductive effects. Questionable
carcinogen with experimental neoplastigenic
and teratogenic data. Human mutation data
reported. A human skin irritant. When
heated to decomposition it emits acrid
smoke and irritating fumes. Used to treat
acne and other skin problems.
Toxicology
Oral retinoic acid has strong teratogenic effects on experimental animals (including mice, rats, hamsters, rabbits, monkeys, etc.) and humans[2]. Topical application of retinoic acid on the skin has clear embryotoxicity and teratogenicity to the mothers of mice, rats, hamsters and rabbits in the embryo sensitive period, and can cause maternal systemic toxicity. However, retrospective data so far have not found teratogenicity after topical administration of human skin. Retinoids are irritating to the skin. The skin reaction of the above-mentioned experimental animals is significantly heavier than the human reaction, which can cause different degrees of skin irritation, inflammation, redness, erosion, weakening of the stratum corneum barrier, increased drug absorption, and systemic toxicity depending on the drug concentration and the number of times of administration. Although external use on human skin is irritating, it does not have the above-mentioned serious reactions. It may be due to differences in skin structure and sensitivity to retinoic acid stimulation between animals and humans. Therefore, the safety data of local administration of retinoic acid in animals and its predictive significance for clinical drug safety should be carefully evaluated.
Veterinary Drugs and Treatments
Topical tretinoin may be useful in treating localized follicular or hyperkeratotic disorders such as acanthosis nigrans, idiopathic nasal and
footpad hyperkeratosis, callous pyodermas, or chin acne. Tretinoin’s exact mechanism of action is not well understood, but it stimulates
cellular mitotic activity, increases cell turnover, and decreases the cohesiveness of follicular epithelial cells.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: possibly increased risk of benign
intracranial hypertension with tetracyclines - avoid.
Antifungals: possible increased risk of tretinoin
toxicity with fluconazole, ketoconazole and
voriconazole.
Vitamin A: risk of hypervitaminosis - avoid.
Metabolism
Metabolised in the liver by the cytochrome P450 isoenzyme system to form isotretinoin, 4-oxo-transretinoic acid, and 4-oxo-cis-retinoic acid. Tretinoin is excreted in the bile and the urine.
Purification Methods
Purify the acid by chromatography on silicic acid columns, and eluting it with a small amount of EtOH in hexane. Also dissolve it in Et2O, wash it with H2O, dry (Na2SO4), evaporate and the solid residue is recrystallised from MeOH (0.53g /3.5mL MeOH to give 0.14g) or EtOH. It also recrystallises from i-PrOH, or as the methyl ester from MeOH. UV in MeOH has max at 351nm ( 45,000). 9-Cis-acid forms yellow needles from EtOH, with m 189-190o, and its UV in MeOH has max at 343nm ( 36,500); the 13-cis-acid forms red-orange plates from i-PrOH with m 174-175o, and UV has max at 345nm ( 39,800). Store it in the dark, in an inert atmosphere, at 0o [Robeson et al. J Am Chem Soc 77 4111 1955]. [Beilstein 9 IV 2387.]
References
1) Allenby (1993), Retinoic acid receptors and retinoid X receptors: interactions with endogenous retinoic acid; Proc. Natl. Acad. Sci. USA, 90 30
2) Dani et . (1997) Differentiation of embryonic stem cells into adipocytes in vitro; J. Cell Sci. 110 1279
3) Hu (2009) Differentiation Of Spinal Motor Neurons From Pluripotent Human Stem Cells; Nat. Protoc., 4 1295
4) Sasai (2002) Generation of dopaminergic neurons from embryonic stem cells J. Neurol., 249 II 41
Check Digit Verification of cas no
The CAS Registry Mumber 302-79-4 includes 6 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 3 digits, 3,0 and 2 respectively; the second part has 2 digits, 7 and 9 respectively.
Calculate Digit Verification of CAS Registry Number 302-79:
(5*3)+(4*0)+(3*2)+(2*7)+(1*9)=44
44 % 10 = 4
So 302-79-4 is a valid CAS Registry Number.
InChI:InChI=1/C20H28O2/c1-15(8-6-9-16(2)14-19(21)22)11-12-18-17(3)10-7-13-20(18,4)5/h6,8-9,11-12,14H,7,10,13H2,1-5H3,(H,21,22)/p-1/b9-6+,12-11+,15-8+,16-14+
302-79-4Relevant articles and documents
A new one-pot synthesis of all E-retinoic acid via a new enaminodiester synthon
Cartier, Dominique,Valla, Alain,Labia, Roger,Le Guillou, Régis,Potier, Pierre
, p. 5789 - 5790 (2003)
A 'one-pot' synthesis of all E-retinoic acid from a new enaminodiester was described. The enaminodiester was easily produced from methyl isopropylidenemalonate and DMF-DMA.
Stereoselective synthesis of all-trans-, (13Z)- and (9-nor)-retinoic acids via Stille reaction
Thibonnet, Jér?me,Abarbri, Mohamed,Duchêne, Alain,Parrain, Jean-Luc
, p. 141 - 143 (1999)
Stereoselective construction of retinoic acid and certain analogues were achieved through two successive Stille reactions. First, the coupling of (E)- 1,2-bis(tributylstannyl)ethene and (Z)- or (E)-tributylstannyl 3-iodoalk-2- enoates was performed followed by iododestannylation. The second step involved another vinyltin which was synthesised by stannylmetallation of the Negishi dienyne derived from β-ionone.
Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes
Harper, Angelica R.,Le, Anh T.,Mather, Timothy,Burgett, Anthony,Berry, William,Summers, Jody A.
, p. 5766 - 5779 (2018)
The retinaldehyde dehydrogenase (RALDH) enzymes, RALDH1, RALDH2, and RALDH3, catalyze the irreversible oxidation of retinaldehyde to all-trans-retinoic acid (ATRA). Despite the importance of the RALDH enzymes in embryonic development, postnatal growth and differentiation, and in several disease states, there are no commercially available inhibitors that specifically target these isozymes. We report here the development and characterization of a small molecule inhibitor dichloro-all-trans-retinone (DAR) (Summers et al., 2017) that is an irreversible inhibitor of RALDH1, 2, and 3 that effectively inhibits RALDH1, 2, and 3 in the nanomolar range but has no inhibitory activity against mitochondrial ALDH2. These results provide support for the development of DAR as a specific ATRA synthesis inhibitor for a variety of experimental and clinical applications.
Impurity analysis of retinoic acid samples
Allegrone, Gianna,Brenna, Elisabetta,Fronza, Giovanni,Fuganti, Claudio,Giovenzana, Tommaso,Malpezzi, Luciana,Barlocchi, Enrico,Pellegatta, Cesare
, p. 3528 - 3531 (2005)
The structure of an impurity contained in samples of all trans-retinoic acid was established by means of NMR and MS spectra, and confirmed by X-ray diffraction analysis. The chemical structure of the impurity 2 was found to be strictly correlated to the s
Synthesis method of new compounds Potassium all-trans retinoate and Potassium 9-cis retinoate.
-
Paragraph 0029-0030, (2021/07/07)
A method for synthesizing all-cis retinoate by adding trans retinoic acid after 9 - cis retinoic acid addition to Hexane-KOH and Potassium all, followed by combining trans retinoate to Potassium all and Potastastastastastastastasy, trans retinoate-cis β LogP-9 which measures the absorption rate at a long time when administered orally, which has an effect of lowering the risk of cancer and cardiovascular diseases carotene. The cardiovascular therapeutic agent of 9, wherein the cardiovascular therapeutic agent is administered orally. The present invention relates to a therapeutic agent for atherosclerosis and a therapeutic agent for angina pectoris.
Iron-Catalyzed Vinylzincation of Terminal Alkynes
Hu, Meng-Yang,Huang, Qiang,Su, Yu-Xuan,Sun, Wei,Wang, Wei-Na,Zhu, Shou-Fei
, (2022/01/08)
Organozinc reagents are among the most commonly used organometallic reagents in modern synthetic chemistry, and multifunctionalized organozinc reagents can be synthesized from structurally simple, readily available ones by means of alkyne carbozincation. However, this method suffers from poor tolerance for terminal alkynes, and transformation of the newly introduced organic groups is difficult, which limits its applications. Herein, we report a method for vinylzincation of terminal alkynes catalyzed by newly developed iron catalysts bearing 1,10-phenanthroline-imine ligands. This method provides efficient access to novel organozinc reagents with a diverse array of structures and functional groups from readily available vinylzinc reagents and terminal alkynes. The method features excellent functional group tolerance (tolerated functional groups include amino, amide, cyano, ester, hydroxyl, sulfonyl, acetal, phosphono, pyridyl), a good substrate scope (suitable terminal alkynes include aryl, alkenyl, and alkyl acetylenes bearing various functional groups), and high chemoselectivity, regioselectivity, and stereoselectivity. The method could significantly improve the synthetic efficiency of various important bioactive molecules, including vitamin A. Mechanistic studies indicate that the new iron-1,10-phenanthroline-imine catalysts developed in this study have an extremely crowded reaction pocket, which promotes efficient transfer of the vinyl group to the alkynes, disfavors substitution reactions between the zinc reagent and the terminal C–H bond of the alkynes, and prevents the further reactions of the products. Our findings show that iron catalysts can be superior to other metal catalysts in terms of activity, chemoselectivity, regioselectivity, and stereoselectivity when suitable ligands are used.
Preparation method of tretinoin
-
Paragraph 0020; 0029; 0031-0032; 0043; 0047; 0051, (2020/05/11)
The invention discloses a preparation method of tretinoin. The method comprises the following steps: 1) hydrolyzing vitamin A acetate under an alkaline condition to obtain vitamin A; and 2) in an oxygen atmosphere, carrying out an oxidation reaction on the vitamin A in an ionic liquid bis-(3-methyl-1-imidazole)ethylene tetrafluoroborate under the catalytic action of RuCl2(PPh3)3 to obtain tretinoin. The method has the advantages of mild reaction conditions, easily available reaction raw materials, no need of purification of intermediates, reaction yield of up to 90%, purity of 99%, and good industrial application prospect.
Catalytic synthesis of 9-cis-retinoids: Mechanistic insights
Kahremany, Shirin,Kubas, Adam,Tochtrop, Gregory P.,Palczewski, Krzysztof
supporting information, p. 10581 - 10595 (2019/07/22)
The regioselective Z-isomerization of thermodynamically stable all-trans retinoids remains challenging, and ultimately limits the availability of much needed therapeutics for the treatment of human diseases. We present here a novel, straightforward approach for the catalytic Z-isomerization of retinoids using conventional heat treatment or microwave irradiation. A screen of 20 transition metal-based catalysts identified an optimal approach for the regioselective production of Z-retinoids. The most effective catalytic system was comprised of a palladium complex with labile ligands. Several mechanistic studies, including isotopic H/D exchange and state-of-the-art quantum chemical calculations using coupled cluster methods indicate that the isomerization is initiated by catalyst dimerization followed by the formation of a cyclic, six-membered chloropalladate catalyst-substrate adduct, which eventually opens to produce the desired Z-isomer. The synthetic development described here, combined with thorough mechanistic analysis of the underlying chemistry, highlights the use of readily available transition metal-based catalysts in straightforward formats for gram-scale drug synthesis.
Z -isomerization of retinoids through combination of monochromatic photoisomerization and metal catalysis
Kahremany, Shirin,Sander, Christopher Lane,Tochtrop, Gregory P.,Kubas, Adam,Palczewski, Krzysztof
supporting information, p. 8125 - 8139 (2019/09/19)
Catalytic Z-isomerization of retinoids to their thermodynamically less stable Z-isomer remains a challenge. In this report, we present a photochemical approach for the catalytic Z-isomerization of retinoids using monochromatic wavelength UV irradiation treatment. We have developed a straightforward approach for the synthesis of Z-retinoids in high yield, overcoming common obstacles normally associated with their synthesis. Calculations based on density functional theory (DFT) have allowed us to correlate the experimentally observed Z-isomer distribution of retinoids with the energies of chemically important intermediates, which include ground- and excited-state potential energy surfaces. We also demonstrate the application of the current method by synthesizing gram-scale quantities of 9-cis-retinyl acetate 9Z-a. Operational simplicity and gram-scale ability make this chemistry a very practical solution to the problem of Z-isomer retinoid synthesis.
Methods for treating of skin conditions with retinoid double conjugate compounds
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Page/Page column 20, (2018/11/30)
A double conjugate molecule made of a retinoid, an organic acid, particularly an a-hydroxy acid, and an alcohol or acyl group, is provided which is useful in treating skin conditions, particularly aging. The retinoid, organic acid, and alcohol/acyl group are preferably linked via ester bonds.
