General Description
Odorless or almost odorless white to off-white crystalline solid. Tasteless.
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).
Air & Water Reactions
Water soluble.
Fire Hazard
Flash point data for this chemical are not available; however, HYDROXYUREA is probably combustible.
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.
Originator
Hydrea,Squibb,UK,1967
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.
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.
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
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
