Hydroxyurea Chemical Properties

Melting point:

135-140 °C

Boiling point:

136.04°C (rough estimate)

Density 

1.457±0.06 g/cm3(Predicted)

refractive index 

1.4840 (estimate)

storage temp. 

2-8°C

solubility 

H₂O: 50 mg/mL

form 

powder

pka

10.56±0.23(Predicted)

color 

white

Odor

odorless or almost odorless

Water Solubility 

soluble

Merck 

14,4848

BRN 

1741548

Stability:

Stable for 2 years as supplied from date of purchase. Solutions in water may be stored at -20°C for up to 3 months.

CAS DataBase Reference

127-07-1(CAS DataBase Reference)

IARC

3 (Vol. 76) 2000

EPA Substance Registry System

Hydroxyurea (127-07-1)

Safety Information

Hazard Codes 

T,Xn

Risk Statements 

46-63-61-40

Safety Statements 

53-36/37-45-36-22

RIDADR 

2811

WGK Germany 

3

RTECS 

YT4900000

Hazard Note 

Toxic

HazardClass 

6.1

PackingGroup 

III

HS Code 

29242100

Hazardous Substances Data

127-07-1(Hazardous Substances Data)

Toxicity

dog,LD50,intravenous,> 1gm/kg (1000mg/kg),Iyakuhin Kenkyu. Study of Medical Supplies. Vol. 23, Pg. 682, 1992.

MSDS

• Language:English Provider:Hydroxyurea
• Language:English Provider:SigmaAldrich
• Language:English Provider:ACROS
• Language:English Provider:ALFA

Hydroxyurea Usage And Synthesis

Drugs and clinical application

Hydroxyurea is a kind of anti-cancer drug for the treatment of chronic myeloid leukemia. At as early as the 1920s, it had been observed that hydroxyurea can cause the rabbits to produce megaloblastic cell similar as pernicious anemia and can inhibit leukocyte generation. In 1963 it had been found of its inhibitory effect on murine leukemia L1210. Hydroxyurea can induce bacteria to produce a toxic molecule itself to achieve the purpose of killing bacteria.
Hydroxy urea is a kind of nucleoside diphosphate reductase inhibitor and can inhibit the reduction from nucleotide to deoxynucleotide, interfering with the biosynthesis of purine and pyrimidine bases and selectively blocking the DNA synthesis. It can also cause partial inhibition of the conversion of ribonucleotides into deoxyribonucleotides. However, it has no blocking effect on RNA and protein synthesis. Hydroxyurea belongs to cycle specific drugs and is sensitive to S phase cell and can induce the hematologic remission of chronic myeloid leukemia. Compared with an alkylating agent busulfan and melphalan, it causes low incidence of secondary leukemia. The myelosuppressive effects of hydroxyurea will last for several days to several weeks which is easier to control compared with the alkylating agent. Clinically hydroxyurea is suitable or the treatment of chronic myeloid leukemia, acute lymphocytic and acute non-lymphocytic leukemia accompanied with high cell count, idiopathic thrombocythemia, polycythemia vera, prevention of retinoic acid syndrome in acute myeloid leukemia and treatment of sickle cell anemia with frequent episodes of pain. In addition, hydroxyurea have a certain effect on the treatment of head and neck cancer, recurrent metastatic ovarian cancer, renal cancer and so on.

Dosage

Adult usual dose:
1. chronic myeloid leukemia, usually the starting dose is daily 20~30mg/kg body weight, take 1 times or 2 times through oral administration; when white cells counts decreases to 10 × 109/L or less, reduce the dose to about 20mg/kg body weight daily with maintained oral administration or changed to oral intermittent administration.
2 for the treatment of head and neck cancer and ovarian cancer; the dose should be 60~80mg/kg body weight each time, or ​​2000~3000mg/m2 (body surface area) with oral administration once every three days. Administrate it alone or in combination with radiotherapy.
This information is edited by Xiongfeng Dai from Chemicalbook.

Adverse reactions, contraindications and the influence of drugs

Myelosuppression was dose-limiting toxicity. Hydroxyurea may cause neutropenia and thrombocytopenia which will disappear at 1 to 2 weeks after discontinuation of the drug; sometimes there may be gastrointestinal reactions, rash, and difficulty in urinating, renal tubular injury as well as testicular atrophy and teratogenesis; there are occasional cases of symptoms of central nervous system and hair loss. It has been also reported that it can cause drug-induced fever which is reproducible under repeated administration. Patients who have allergies, platelets being less than 50 × 109/L, chickenpox, shingles and various kinds of serious infections should be disabled. Pregnant and lactated women should also be disabled. Hydroxyurea can reduce the extent of 5-FU’s being converted into the active metabolite therefore it should be cautious when being taken together. When using hydroxyurea, we should be cautious if need to administrate barbiturates, antipsychotics and anesthetics; when hydroxyurea is combined with allopurinol, colchicine, probenecid for the treatment of gout, the dose of the above drugs should be adjusted. Avoid viral vaccination during treatment. The patients can only be subject to vaccination after discontinuing the drug for three months to one year. Upon taking hydroxyurea sheet, you should appropriately increase the fluid intake amount to increase the amount of urine and excretion of uric acid. The patients should also be subject to regular monitoring of white blood cells, platelets, blood urea nitrogen, uric acid level and inosine concentrations.

Chemical Properties

It appears as white needle-like crystals with the melting point being 70-72 ℃ (decomposition) or 141 ℃ (decomposition). It is easily soluble in hot water and ethanol, slightly soluble in cold ethanol, insoluble in ether, benzene. It is unstable when coming across water or heat. It is odorless and tasteless.

Uses

It belongs to anti-metabolic anti-cancer drugs with its major role in the proliferation of cells in G1 and S phase. It also had delayed effect on G1/S interface. It is a cell-specific drug.
It can be applied to biochemical studies.
Through the formation of free nitric oxide, it binds to the tyrosine of the enzyme active site, leaving the nucleoside reductase inactivated. This hampers the synthesis of deoxynucleotide. It is clinically used for the treatment of chronic myelogenous leukemia as well as being used to treat metastatic ovarian cancer, head and neck primary squamous cell carcinoma and intractable psoriasis. The good belongs to anticancer drugs.

Production method

It is produced through the reaction between ethyl carbamate and hydroxylamine hydrochloride. The sodium hydroxide solution was cooled to 20-25 ℃. Add alternately under stirring of urethane and hydroxylamine hydrochloride and react at 25-28 ℃ for 16h. Use hydrochloric acid to neutralize to a pH of 6.5-7, control the temperature be not exceeding 25 ℃. Then apply concentration under reduced pressure, filtered hot and the filtrate was cooled to below 0 ℃ to precipitate our the crystal, filter, wash crystal with ice water, and dry to give crude hydroxyurea with the yield of about 65%. After refining, we can obtain pharmaceutical grade hydroxyurea.

Description

Readily oxidized in vivo to free radical forms, which destroy the stable tyrosyl free radical of the metalloenzyme ribonucleotide reductase, suppressing deoxyribonucleotide production and blocking DNA synthesis and repair.1,2 Reduces cell proliferation, and causes S-phase arrest and death.3 Induces p53-dependent NF-κB target gene expression in U2OS cells expressing HA-RelA.4 Stimulates fetal hemoglobin production in vitro and in vivo.5 Allows for S phase enrichment of CHO cells with maintenance of viability for enhanced site-specific genome engineering.6 Anticancer and antiviral agent.

Chemical Properties

Off-White Crystalline Solid

Originator

Hydrea,Squibb,UK,1967

Uses

Hydroxyurea USP is used to treat Chronic granulocytic leukemia; melanoma; cancer of ovary, head, neck.

Uses

An anti-neoplastic - inhibits ribonucleoside reductase and DNA replication. A potential therapy for sickle cell anemia which involves the nitrosylation of sickle cell hemoglobin. Horseradish peroxidase catalyzes nitric oxide formation from hydroxyurea in the presence of hydrogen peroxide.

Uses

antineoplastic, inhibits ribonucleoside diphosphate reductase

Indications

Hydroxyurea (Hydrea) inhibits the enzyme ribonucleotide reductase and thus depletes intracellular pools of deoxyribonucleotides, resulting in a specific impairment of DNA synthesis. The drug therefore is an Sphase specific agent whose action results in an accumulation of cells in the late G1- and early S-phases of the cell cycle.

Definition

ChEBI: Hydroxyurea is a member of the class of ureas that is urea in which one of the hydrogens is replaced by a hydroxy group. An antineoplastic used in the treatment of chronic myeloid leukaemia as well as for sickle-cell disease. It has a role as a DNA synthesis inhibitor, an EC 1.17.4.1 (ribonucleoside-diphosphate reductase) inhibitor, an antineoplastic agent, a genotoxin, an antimetabolite, a teratogenic agent, a radical scavenger, an immunomodulator and an antimitotic. It is a member of ureas and a one-carbon compound.

Manufacturing Process

The procedure may be illustrated by the following equations relating to the preparation of hydroxyurea from hydroxylamine hydrochloride:
(1) R4N+Cl-+ NaNCO = R4N+NCO-+ NaCl
(2) R4N+NCO-+ H2NOH HCl = R4N+Cl-+HONH-CO-NH2
Equation (1) shows the simple conversion of a quaternary ammonium anion exchange resin from the chloride form to the cyanate form. Equation (2) shows the reaction of the resin in the cyanate form with hydroxylamine hydrochloride whereby hydroxyurea is formed and the anion Cl-is retained by the quaternary resin.
A 90 x 6 cm column was packed with 2 kg of granular Amberlite IRA-410 resin in the chloride form (a vinylpyridine/divinylbenzene copolymer quaternized with dimethyl sulfate and converted to chloride) and washed with 3 kg of a 10% aqueous solution of sodium cyanate. This changed the resin from the chloride to the cyanate form. Sodium chloride and excess sodium cyanate were then washed from the column with distilled water until the effluent failed to give a white precipitate with silver nitrate. The reaction of equation (2) was conducted by elutriating the column with a solution of 105 grams (1.5 mols) of hydroxylamine hydrochloride in 400 ml water at about 15°C.
A hot (50° to 70°C) reaction zone developed near the top of the column and about 30 minutes was required for this hot zone to descend the full length of the column. The reaction solution was followed in the column by 2.5 liters of distilled water. Collection of the product was begun when hydroxyurea could be detected in the effluent, as indicated by a black precipitate on warming a sample with a silver nitrate test solution. All the effluents were combined and vacuum evaporated at 35°C to give 90 grams of tan residue corresponding to 79% yield of crude product. After recrystallization from 100 ml of water heated to 75°C, the colorless product was dried in a vacuum desiccator over phosphorus pentoxide to give 60.6 grams (53% yield) of hydroxyurea, MP 133° to 136°C.

Therapeutic Function

Cancer chemotherapy

General Description

Odorless or almost odorless white to off-white crystalline solid. Tasteless.

General Description

HONH-CO-NH₂. The drug is available in a 500-mg capsulefor oral use. Hydroxyurea is often considered an antimetabolitedrug, and it is used to treat myelogenousleukemia, ovarian cancer, and essential thrombocytosis. Themechanism of action of hydroxyurea involves inhibition ofDNA biosynthesis by inhibition of the enzyme ribonucleotidereductase). Resistance can occur viaincreased expression of ribonucleotide reductase. The oralbioavailability is quite high approaching 100% and the drugis distributed to all tissues. Hydroxyurea readily enters theCNS and distributes to human breast milk. A major portionof the total dose is excreted unchanged in the urine. Thedrug has been shown to increase the toxicity of 5-FU, andhydroxyurea may increase the effectiveness of some antimetaboliteHIV drugs. The toxicity profile includes myelosuppression,leucopenia, nausea, vomiting, pruritus hyperpigmentation,headache, drowsiness, and confusion.

Air & Water Reactions

Water soluble.

Reactivity Profile

An amide. Amides/imides react with azo and diazo compounds to generate toxic gases. Flammable gases are formed by the reaction of organic amides/imides with strong reducing agents. Amides are very weak bases (weaker than water). Mixing amides with dehydrating agents such as P2O5 or SOCl2 generates the corresponding nitrile. The combustion of these compounds generates mixed oxides of nitrogen (NOx).

Fire Hazard

Flash point data for Hydroxyurea are not available; however, Hydroxyurea is probably combustible.

Biochem/physiol Actions

Anti-neoplastic. Inactivates ribonucleoside reductase by forming a free radical nitroxide that binds a tyrosyl free radical in the active site of the enzyme. This blocks the synthesis of deoxynucleotides, which inhibits DNA synthesis and induces synchronization or cell death in S-phase.

Mechanism of action

Hydroxyurea is rapidly absorbed after oral administration, with peak plasma levels achieved approximately 1 to 2 hours after drug administration; its elimination half-life is 2 to 3 hours. The primary route of excretion is renal, with 30 to 40% of a dose excreted unchanged.

Clinical Use

Hydroxyurea is used for the rapid lowering of blood granulocyte counts in patients with chronic granulocytic leukemia. The drug also can be used as maintenance therapy for patients with the disease who have become resistant to busulfan. Only a small percentage of patients with other malignancies have had even brief remissions induced by hydroxyurea administration.

Side effects

Hematological toxicity, with white blood cells affected more than platelets, may occur. Megaloblastosis of the bone marrow also may be observed. Recovery is rapid, generally within 10 to 14 days after discontinuation of the drug. Some skin reactions, including hyperpigmentation and hyperkeratosis, have been reported with chronic treatment.

Synthesis

Hydroxyurea (30.6.1) is made by reacting sodium cyanate with hydroxylamine. In this reaction, hydroxylamine hydrochloride and a basic ion-exchange resin are used.

Veterinary Drugs and Treatments

Hydroxyurea may be useful in the treatment of polycythemia vera, mastocytomas, and leukemias in dogs and cats. It is often used to treat dogs with chronic myelogenous leukemia no longer responsive to busulfan. Hydroxyurea, potentially, may be of benefit in the treatment of feline hypereosinophilic syndrome and in the adjunctive treatment of canine meningiomas. It can also be used in dogs for the adjunctive medical treatment (to reduce hematocrit) of right to left shunting patent ductus arteriosis or tetralogy of Fallot.

Drug interactions

Potentially hazardous interactions with other drugs
Antipsychotics: avoid with clozapine, increased risk of agranulocytosis.
Antivirals: increased toxicity with didanosine and stavudine - avoid.
Vaccines: risk of generalised infections - avoid.

Metabolism

Hydroxyurea has excellent oral bioavailability (80–100%), and serum levels peak within 2 hours of consuming the capsules. If a positive response is noted within 6 weeks, toxicities generally are mild enough to permit long-term or indefinite therapy on either a daily or every-3-day basis. Leukopenia and, less commonly, thrombocytopenia and/or anemia are the most serious adverse effects. Excretion of the unchanged drug and the urea metabolite is via the kidneys. The carbon dioxide produced as a by-product of hydroxyurea metabolism is excreted in the expired air.

Purification Methods

Recrystallise hydroxyurea from absolute EtOH (10g in 150mL). Note that the rate of solution in boiling EtOH is slow (15-30minutes). It should be stored in a cool dry place, but some decomposition could occur after several weeks. [Deghenghi Org Synth Coll Vol V 645 1973.] It is very soluble in H2O and can be crystallised from Et2O. [Kfod Acta Chem Scand 10 256 1956, Beilstein 3 IV 170.]

References

Gr?sland et al. (1985), The tyrosyl free radical in ribonucleotide reductase; Health Perspect., 64 139 Yarbro (1992), Mechanism of action of hydroxyurea; Oncol., 3 (Suppl 9) 1 Singh and Xu (2016), The Cell Killing Mechanisms of Hydroxyurea; Genes (Basel), 7 99 Campbell et al. (2021), Temporal modulation of the NF-kB Re1A network in response to different types of DNA damage; J., 478 533 Baliga et al. (2000), Mechanism for fetal hemoglobin induction by hydroxyurea in sickle cell erythroid progenitors; J. Hematol., 65 227 Kwak et al. (2021), Hydroxyurea selection for enhancement of homology-directed targets integration of transgenes in CHO cells; Biotechnol, 62 26

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