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| Product Name: | (+)-Griseofulvin | | Synonyms: | 7-Chloro-2,4,6-trimethoxy-6-methyl-, (1S-trans)-Spiro(benzofuran-2(3H),1-(2)cyclohexene)-3,4-dione;Grisovi;Griseofulvin, (2S)-trans-7-Chloro-2μ,4,6-trimethoxy-6μ-methylspiro(benzofuran-2[3H],1μ-[2]cyclohexene)-3,4μ-dione;7-Chloro-2',4,6-trimethoxy-6'b-methylspiro[benzofuran-2(3H),1'-[2]cyclohexene]-3,4'-dione;Grisact;(+)-Griseofulvin,97%;GRISEOFULVIN(RG);Griseofulvin (200 mg) | | CAS: | 126-07-8 | | MF: | C17H17ClO6 | | MW: | 352.77 | | EINECS: | 204-767-4 | | Product Categories: | VERELAN;Intermediates & Fine Chemicals;Pharmaceuticals;Antifungal;Aromatics;Chiral Reagents;Inhibitors;126-07-8 | | Mol File: | 126-07-8.mol |  |
| | (+)-Griseofulvin Chemical Properties |
| Melting point | 218-220 °C(lit.) | | alpha | 354 º (c=1, dimethylform) | | Boiling point | 469.04°C (rough estimate) | | density | 1.2579 (rough estimate) | | refractive index | 1.4429 (estimate) | | storage temp. | 2-8°C | | solubility | Practically insoluble in water, freely soluble in dimethylformamide and in tetrachloroethane, slightly soluble in anhydrous ethanol and in methanol | | form | Powder | | color | White to yellow-white | | Water Solubility | practically insoluble | | λmax | 321nm(CHCl3)(lit.) | | Merck | 14,4549 | | BRN | 95226 | | BCS Class | 2 (CLogP), 4
(LogP) | | Stability: | Stable for 1 year from date of purchase as supplied. Solutions in DMSO, ethanol, or DMF may be stored at -20° for up to 3 months. | | InChIKey | DDUHZTYCFQRHIY-RBHXEPJQSA-N | | LogP | 2.180 | | CAS DataBase Reference | 126-07-8(CAS DataBase Reference) | | IARC | 2B (Vol. Sup 7, 79) 2001 | | NIST Chemistry Reference | Griseofulvin(126-07-8) | | EPA Substance Registry System | Griseofulvin (126-07-8) |
| | (+)-Griseofulvin Usage And Synthesis |
| General description | Griseofulvin is a non-polyene class antifungal antibiotics; it can strongly inhibit the mitosis of fungal cell and interfere with the fungal DNA synthesis; it can also bind to tubulin to prevent fungal cell division. It has been applied to clinical medicine since 1958 and has currently been widely used for treating the fungal infections of the skin and the stratum corneum with strong inhibitory effects on Trichophyton rubrum and Trichophyton tonsorans, etc. Griseofulvin is not only a widely used antibiotic for clinical treatment of fungal infections of the skin and cuticle, but also applied in agriculture for prevention and treatment of fungal diseases; for example, it has a special efficacy on treating a kind of candidiasis in apple which can cause infection during pollination.
| | Physical and Chemical Properties | Griseofulvin pure product is colorless crystal, being neutral, and insoluble in water with a strong systemic property. It is stable both in vitro and in vivo of plants and is also stable to the various environment factors between pH3.0~8.8. It can be used for prevention and treatment of a variety of fungal plant diseases. The main species china applied for production of griseofulvin is Penicillium nigricans and Penicillium urticae. When grown at the medium, Penicillium nigricans is fuzzy with fresh culture being pure gray and aging culture being dark gray with its back being deep orange-red to the back orange brown. The fungi lawn of Penicillium urticae is yellowish green to pure light gray, thick and dense with the back being pale yellow to brownish; their aerial hyphae has a broom-like shape.
The above information is edited by the chemicalbook of Dai Xiongfeng.
| | Pharmacological effects | In medicine, this product mainly has good antibacterial effect against Trichophyton, Microspores, and Epidermophyton fungi. However, it has no anti-bacterial effect on Candida, Cryptococcus, Histoplasma, Sporothrix, Blastomyces, and Coccidioides and so on. Mechanism of action of is drug is through interfering with the biosynthesis of nucleic acids of fungal and further inhibiting of its growth.
In agriculture, this product has good inhibitory effect on the Ascomycetes, Basidiomycetes, Deuteromycetes and some kinds of algae. However, it is not effective in treating oomycetes whose cell wall containing no chitin content. After spraying melons and other crops, it can be transferred into the branch, leaves and fruits through inner absorption, the absorption of water via rrot, as well as transpiration effect, and further preventing the fungal diseases; according to the study of Brandeis et al. (1946), at a concentration as low as even 10 mg/L or 1 mg/L, griseofulvin can already can make the mycelium of Bctrytis allill be stout, deformed and exhibit spiral bending, also cause: large number of abnormal branching; the development retardation of germinated spores, and loss of apical dominance; thus it has uptake therapeutic effects on a variety of plant diseases, especially powdery mildew, gray mold diseases; Griseofulvin has a more prominent antibacterial activity than the bactericidal activity.
| | Pharmacokinetics | The absorption of orally administration of this drug varies according to the difference in preparation, the micro-particle of this drug can be absorbed by 25% to 70%; its ultrafine particles can almost all absorbed after oral administration. Eating fat can significantly increase the extent of absorption. The product has a serum protein binding rate of being 80%. After its absorption, this product can be deposited in the skin, hair, nail cuticle and combine with keratin to prevent the further invasion of sensitive dermatophytes; at the same time, the pathogenic fungi locate in superficial stratum corneum will leave the body together with the fall-off of the skin or hair with only a very small amount being distribution in other body fluids and tissues. This product can also enter into the fetal circulation and be secreted from the milk. This product is inactivated through metabolism in the liver with the main metabolite being 6-methyl griseofulvin and glucuronic acylate; the blood elimination half-life is 14 to 24 hours. The percentage of product secreted from the urine in its prototype is less than 1% with about 16% to 36% of the prototype being discharged from the feces.
| | Indications | In medicine, this product is suitable for the treatment of a variety of ringworm, including tinea capitis, tinea barbae, body tinea, jock itch, foot tinea and onychomycosis. The various kinds of tinea mentioned are caused by various fungi including Trichophyton rubrum, Trichophyton tonsorans, Trichophyton mentagrophytes, Fingers Trichophyton, etc., and Microsporon audouini, Microsporon canis, Microsporon gypseum and Epidermophyton floccosum, etc. due. This product is not suitable for treatment in mild cases, localized infection cases and cases which can be treated with topical antifungal agents. Griseofulvin is not effective in treating the infections of a various kinds of fungi such as Candida, Histoplasma, Actinomyces, Sporothrix species, Blastomyces, Coccidioides, Nocardio and Cryptococcus species as well as treating tinea versicolor.
In agriculture, this product is first introduced by Brian et al (1951) for control of plant diseases. According to previous studies, it can be used for prevention of melon (melon) vine blight, crack spread disease, watermelon blight, anthracnose, apple blossom rot, apple cold rot, apple rot, cucumber downy mildew , strawberry gray mold, gourds hanging blight, powdery mildew of roses, chrysanthemums powdery mildew, rot flower lettuce, early tomato blight, tulip fire blight and other fungal diseases.
| | Side effects | 1. Nervous system headache is relatively common with about 10% of patients experiencing headaches; it is a bit severe at initial stage, but will be alleviated with the continuing administration of drug; other reactions also include lethargy and fatigue. Occasional dizziness, ataxia, and peripheral neuritis may also occur.
2. For Digestive system; a small number of patients may undergo abdominal discomfort, nausea or diarrhea, usually mild which can be tolerated by the patient.
3. Allergies can occur in about 3% of patients which suffers rash; occasionally angioneurotic edema, persistent urticaria, and exfoliative dermatitis can also occur; in very rare cases, photosensitive dermatitis can occur at a small number of patients.
4. This product can sometimes cause reduction of the number of peripheral blood leukocyte; sometime can even cause liver toxicity and proteinuria.
| | Precautions | 1. Cross allergy; because griseofulvin is obtained from Penicillium, which indicated that the drug may have cross-allergy with penicillin or penicillamine, however, this kinds of hypothesis hasn’t been confirmed by clinical cases; but patients allergic to penicillin should still apply with caution and subject to careful observation.
2. Griseofulvin can cause tumor in animal experiments.
3. This product can occasionally cause liver toxicity; patients with original liver disease or liver damage should decide whether to choose to apply this drug after thinking twice.
4. It can induce porphyria and lupus; lupus patients who have index should have trade-off decision before applying this drug.
5. During the treatment, regular testing of peripheral blood, liver function, blood nitrogen content in urea, creatinine and urine routine are demanded.
6. It can be administrated either simultaneously with meal or after the meal with high-fat meal being the best, because they can reduce the gastrointestinal side effects and increase drug absorption.
7. In order to prevent relapse, treatment should be continued until clinical symptoms and laboratory tests confirmed that the pathogen has been completely eradicated. Usually treatment course is: tinea capitis: 8 to 10 weeks; tinea: 2 to 4 weeks; tinea pedis: 4-8 weeks; finger nail tinea: at least four months; nail psoriasis: at least six months, although still with a high recurrence rate.
8. A suitable topical administration is usually necessary at the same time; this is particularly important for athlete's foot.
9. During the treatment or at least 6 months of post-treatment, male patients should take contraceptive measures for prevention of pregnancy.
| | Drug Interactions | 1. Combination of this product together with ethanol can cause tachycardia, sweating, flushing of the skin, etc., so avoid taking them at the same time.
2. Combination with anticoagulant drugs such as warfarin, and coumarin can enhance the hepatic metabolism and leaving the efficacy of anticoagulation being weakened; so it is necessary to adjust the dose by monitoring the prothrombin time at the same time.
3. Combination with primidone, and phenobarbital can decrease the antifungal effect of this product which may be due to that absorption of barbiturates may reduce the absorption of this drug as well as the increased rate of its inactivation due to the induction of hepatic enzyme which causes the decreased blood concentration; thus should avoid this kind of combination of drugs.
4. Combination of estrogen-class contraceptive with the product can reduce the effect of orally administrated contraceptives which may be due to that the product may strengthen the metabolism of contraceptive drugs in the live, causing its decreased blood concentration; thus should avoid using them simultaneously.
| | Toxicity | Griseofulvin has a relatively low toxicity to warm-blooded animals; intraperitoneal injection of both sexes of Waster rats found that they could both withstand a dosage of per 100ml/kg (some damage effects on the seminal vesicles and the intestinal epithelium were observed). Although intravenous injection can cause the temporary inhibition of cells mitosis (especially bone marrow some cells), the rates were almost unaffected under normal conditions. Moreover, after 24 hours, the rats began to rapidly recover; its LD50 is 400ml/kg body weight. Furthermore, even a large dose of griseofulvin only has a very small toxicity to the plants. It will be slowly degraded in the body with a faster degradation rate in soil; so there are no issues about residue and environmental pollution problems. However, the property of its fast degradation also limits their application of antimicrobial activity in agriculture.
| | Pediatric medication | We are lack of information about the medication on children under 2 years.
| | Elderly medication | There are still no existing information about its application in Elderly people and the relation with their ages.
| | Chemical Properties | It is white or white-like powder. Melting point is 218-224 °C. It is highly soluble in tetrachloroethane, soluble in acetone or chloroform, slightly soluble in methanol or ethanol, and very slightly soluble in water. It is odorless or almost odorless with slightly bitter taste. It is stable to heat.
| | Production methods | Griseofulvin is a antibiotic produced from the culture fermentation broth of Penicillium griseofulvum.
| | Category | Pesticide
| | Toxicity grading | Low toxicity
| | Acute toxicity | Oral-rat LD50: 10000 mg/kg; Oral-Mouse LD50: 50000 mg/kg
| | Flammability hazard characteristics | Combustion can produce toxic chloride gas
| | Storage Characteristics | Treasury: ventilation low-temperature an dry; it should be separately stored and transported from raw materials of food.
| | Extinguishing agent | Dry powder, foam, sand
| | Description | Griseofulvin (126-07-8) is an antifungal antimitotic agent. Induces apoptosis of human germ cell tumor cells via disruption of connexin 43/tubulin association concomitant with enhanced translocation of connexin 43 from the cytoplasm to the nucleus.1?Inhibits the growth of adrenocortical cancer cells?in vitro.2 Griseofulvin inhibits centrosome clustering, induces spindle multipolarity, mitotic arrest and cell death in multiple tumor cell lines but not in diploid fibroblasts and keratinocytes with normal centrosome content.3 | | Chemical Properties | Crystalline Solid | | Originator | Grifulvin,McNeil,US,1959 | | Uses | adrenegic blocker, Ca channel blocker, coronary vasodilator, antiarrhythmic | | Uses | antifungal, inhibits mitosis in metaphase | | Uses | Griseofulvin is a spirobenzofuran produced by a number of Penicillium species, first isolated in the 1930s by Raistrick's group. Griseofulvin is a selective antifungal agent used to treat skin infections in animals and humans. Griseofulvin acts by binding to fungal tubulin and inhibiting the mitotic spindle. Griseofulvin's ability to bind to keratin is considered an important aspect of the metabolite's access to dermatophytic fungi. More recently, griseofulvin has become an important phenotypic marker in Penicillium taxonomy. | | Uses | An antifungal and antiproliferative agent that affects microtubules. | | Uses | It is an antifungal drug. It is used both in animal and in humans, to treat rigworm infections of the skin and nails. It is derived from the mold Penicillium griseofulvum.Environmental contaminants; Food contaminants. | | Definition | ChEBI: An oxaspiro compound produced by Penicillium griseofulvum. It is used by mouth as an antifungal drug for infections involving the scalp, hair, nails and skin that do not respond to topical treatment. | | Indications | Griseofulvin (Fulvicin, Grifulvin V) has been used
safely and effectively for decades for dermatophyte infections
of scalp and nails and for more widespread skin
eruptions. However, infections in certain sites (e.g.. toenails)
respond poorly. The drug is generally well tolerated,
even in the long-term courses necessary for nail
disease. | | Indications | Griseofulvin (Gris-PEG, Grifulvin, Grisactin, Fulvicin) is
an oral fungistatic agent used in the long-term treatment
of dermatophyte infections caused by Epidermophyton,
Microsporum, and Trichophyton spp. Produced by the
mold Penicillium griseofulvin, this agent inhibits fungal
growth by binding to the microtubules responsible for
mitotic spindle formation, leading to defective cell wall
development.
Ineffective topically, griseofulvin is administered
orally but has poor gastrointestinal absorption; absorption
can be improved by microcrystalline processing of
the drug and by taking the drug with fatty meals. Peak
serum levels occur 4 hours after dosing. Griseofulvin is
metabolized in the liver and has a half-life of 24 to 36
hours. The drug binds to keratin precursor cells and
newly synthesized keratin in the stratum corneum of
the skin, hair, and nails, stopping the progression of dermatophyte infection. | | Manufacturing Process | The experiment was carried out on the 1,000 gallon scale. Three impellers
1'8" diameter at 220 rpm were employed. The air rates were 0 to 5 hours, 40
cfm, 5 to 10 hours, 80 cfm and after 10 hours, 125 cfm. The inoculum rate
was 10% v/v. It was prepared by the standard inoculum development
technique on the following medium:
This was inoculated with a spore suspension of P. patulurn (1 liter containing
3-5 x 107 spores/ml) and grown at 25°C in 100 gallon tank. The inoculum is
transferred at 40 hours or when the mycelial volume (after spinning 10
minutes at 3,000 rpm) exceeds 25%. The fermentation is conducted as near
to the ideal pH curve as possible by addition of crude glucose, according to US
Patent 3,069,328. | | Brand name | Fulvicin Bolus [Veterinary]
(Schering-Plough Animal Health); Fulvicin-P/G (Schering);
Fulvicin-U/F (Schering); Fulvicin-U/F Powder and
Tablets [Veterinary] (Schering-Plough Animal Health);
Grifulvin V (Ortho Pharmaceutical); Grisactin (Wyeth-
Ayerst); Gris-PEG (Allergan Herbert);B-gf;Delmofluvina;Flugolin;Fulcine-125;Fulcine-s;Fulvicin p/g;Fulvicin u/f;Fulvicina;Gefulvine;Grfulvin v;Grisaltin;Grisefalin;Grisefulvin;Griseomed;Griseostatin;Grisovina fp;Grisovine;Grisovin-fp;Grisowen;Lamoryl-novum;Lamoyl;Likuden m;Microcidal;Neo fulcin;Neo-filcin;Norofluvin;Ocufen;Sulvina. | | Therapeutic Function | Antifungal | | World Health Organization (WHO) | Griseofulvin, isolated from a penicillin producing mould, has
been widely used as a systemically administered antifungal agent in man for over
20 years. It is effective in dermatophyte infections (including tinea barbae and tinea
capitis) but it is inactive against yeasts and bacteria. Evidence that very high doses
of griseofulvin are carcinogenic, teratogenic and fetotoxic in laboratory animals
has led to an acceptance that it should not be used to treat trivial infections that respond to topical therapy. Oral formulations of griseofulvin are included in the
WHO Model List of Essential Drugs.
(Reference: (WHTAC1) The Use of Essential Drugs, 2nd Report of the WHO Expert
Committee, 722, , 1985) | | Antimicrobial activity | The spectrum of useful activity is restricted to dermatophytes
causing skin, nail and hair infections (Epidermophyton,
Microsporum and Trichophyton spp.). Resistance has seldom
been reported. | | General Description | White to pale cream-colored crystalline powder. Odorless or almost odorless. Tasteless. Sublimes without decomposition at 410°F. | | Air & Water Reactions | Insoluble in water. | | Reactivity Profile | (+)-Griseofulvin is incompatible with strong oxidizing agents. . | | Hazard | Possible carcinogen. | | Fire Hazard | Flash point data for (+)-Griseofulvin are not available. (+)-Griseofulvin is probably combustible. | | Pharmaceutical Applications | A fermentation product of various species of Penicillium,
including Pen. griseofulvum. Available as fine-particle or ultrafine-
particle formulations for oral use. | | Mechanism of action | The mechanism of action of griseofulvin is through binding to the protein tubulin, which interferes with the function of the mitotic spindle and, thereby, inhibits cell division. Griseofulvin also may interfere directly with DNA replication. Griseofulvin is gradually being replaced by newer agents . | | Pharmacokinetics | Absorption from the gastrointestinal tract is dependent on drug
formulation. Administration with a high-fat meal will increase
the rate and extent of absorption, but individuals tend to achieve
consistently high or low blood concentrations. It appears in the
stratum corneum within 4–8 h as a result of secretion in perspiration.
However, levels begin to fall soon after the drug is
discontinued, and within 48–72 h it can no longer be detected.
It is metabolized in the liver, the metabolites being excreted in
the urine. The elimination half-life is 9–21 h. | | Clinical Use | In the treatment of ringworm of the beard, scalp,
and other skin surfaces, 4 to 6 weeks of therapy is often
required. Therapy failure may be to the result of an incorrect
diagnosis; superficial candidiasis, which may resemble
a dermatophyte infection, does not respond to
griseofulvin treatment. Onychomycosis responds very
slowly to griseofulvin (1 year or more of treatment is
commonly required) and cure rates are poor; itraconazole
and terbinafine hydrochloride are more effective
than griseofulvin for onychomycosis. | | Clinical Use | Dermatophyte infections of hair, skin and nail | | Side effects | Adverse reactions occur in about 15% of patients and include
headache, nausea, vomiting, rashes and photosensitivity. | | Side effects | Griseofulvin is usually well tolerated. Headache is
common with initiation of therapy. Hepatotoxicity (especially
in patients with acute intermittent porphyria),
dermatitis, and gastrointestinal distress also occur.
Griseofulvin increases warfarin metabolism, and griseofulvin
metabolism is increased by phenobarbital. | | Synthesis | Griseofulvin, 7-chloro-2,4,6-trimethoxy-6-methylspiro[benzofuran-
2(3H),1-[2]-cyclohexen]-3,4-dione (35.4.1), is an antibiotic produced by the mycelial
fungus Penicillium patulum. | | Veterinary Drugs and Treatments | In veterinary species, griseofulvin is approved for use in dogs and
cats to treat dermatophytic fungal (see below) infections of the skin,
hair and claws, and to treat ringworm (caused by T. equinum and
M. gypseum) in horses. It has also been used in laboratory animals
and ruminants for the same indications. The oral tablets approved
for dogs and cats are no longer marketed in the USA, but human
dosage forms are available. | | Drug interactions | Potentially hazardous interactions with other drugs
Anticoagulants: metabolism of coumarins accelerated
(reduced anticoagulant effect).
Ciclosporin: griseofulvin possibly reduces ciclosporin
concentration (two reports of such an interaction in
literature).
Oestrogens and progestogens: metabolism of oral
contraceptives accelerated (reduced contraceptive
effect).
Ulipristal: possibly reduced contraceptive effect -
avoid. | | Metabolism | Griseofulvin is metabolized by the liver, and its metabolites are excreted
in the urine. It is highly protein bound and, therefore, may have high tissue
levels. However, tissue levels decrease and fall as soon as griseofulvin is
discontinued such that its presence is no longer detectable 2 to 3 days after
cessation of therapy. | | Purification Methods | Crystallise it from *benzene or EtOH. Purify 2g of griseofulvin by chromatography on Alumina (40 x 1.5cm) and elute with *C6H6/MeOH (199:1) and follow the UV blue fluorescent band. [MacMillan J Chem Soc 1823 1959, Beilstein 18 III/IV 3160, 18/5 V 150.] | | Dosage forms | The average treatment time for tinea capitis is 4 to 6 weeks; for tinea
corporis, 2 to 4 weeks; and for tinea pedis, 4 to 8 weeks. Because of the
low cure rate and length of therapy, griseofulvin is not commonly used for
onychomycosis of the fingernails or toenails. Complete blood count (CBC)
is monitored every 3 months during long-term therapy. | | References | 1) Mauro?et al. (2013),?The anti-mitotic drug griseofulvin induces apoptosis of human germ cell tumor cells through a connexin 43-dependent molecular mechanism; Apoptosis,?18?480
2) Bramann?et al. (2013),?Griseofulvin inhibits the growth of adrenocortical cancer cells in vitro; Horm. Metab. Res.,?45?297
3) Rebacz?et al. (2007),?Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype-based screen; Cancer Res., 67?6342 |
| | (+)-Griseofulvin Preparation Products And Raw materials |
| Raw materials | Starch-->Oxalic acid-->CORN STEEP LIQUOR-->Spiro[benzofuran-2(3H),1'-[2]cyclohexene]-3,4'-dione, 7-chloro-2'-hydroxy-4,6-dimethoxy-6'-methyl-, (1'S,6'S)--->Ethanone, 1-(3-chloro-2-hydroxy-4,6-dimethoxyphenyl)--->Spiro[benzofuran-2(3H),1'-[2,5]cyclohexadiene]-3,4'-dione, 7-chloro-2',4,6-trimethoxy-6'-methyl--->2-chloro-3,5-dimethoxyphenol(WXC05665) | | Preparation Products | 4'-O-DeMethyl Griseofulvin |
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