Hydroxyurea

Hydroxyurea suppresses DNA synthesis by inhibiting ribonucleoside diphosphate reductase, which catalyzes the reduction of ribonucleotides to deoxyribonucleotides. Hydroxyurea is used in chronic cases of granulocytic leukemia that are unresponsive to busulfan. In addition, it is used for acute lymphoblastic leukemia. Hydroxyurea may cause bone marrow depression. 

4 Hydroxyurea. - Hydroxyurea, H2NC(0)NH0H, is used in the treatment sickle cell disease and myeloproliferative disorders. The interaction of HU with Hb-Fe(Il)-02 results in the production of Hb-Fe(II)-NO, Hb-Fe(III) and NOu. The anti-proliferative action of HU results from its inhibition of ribonucleotide reducase (a key enzyme in DNA synthesis), which is believed to involve the reaction of NO with a tyrosyl radical formed during the reaction cycle. King et 

Therapeutic Function Cancer chemotherapy Chemical Name Hydroxycarbamide Common Name — 

Structural Formula HjNCONHOH Chemical Abstracts Registry No. 127-07-1 

Trade Name Manufacturer Country Year Introduced 

The procedure may be illustrated by the following equations relating to the preparation of hydroxyurea from hydroxylamine hydrochloride  

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. 

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Those herbicides that block mitotic entry decrease or prevent the formation of mitotic figures in meristems. Amino acid, protein, RNA, DNA, and ATP synthesis and/or utilization can all attest cell growth (163,166). Although not registered as herbicides, cycloheximide [66-81-9] inhibits mitotic entry by inhibiting protein synthesis (167) hydroxyurea/727-(97-/7 inhibits DNA synthesis (168) and actinomycin D [50-76-0] nh2oix.s RNA synthesis (167). 

Ketones react with formaldehyde and perchloric acid to produce 2-isoxazolines and also with urea in a-methylnaphthalene at 200 °C (75MIP41600, 75ZOB2090, 79MI41612) with N-hydroxyurea they produce 3-hydroxy-2-carbamoylisoxazolidines or, after acid treatment, 2-isoxazolines are formed (Scheme 123) (75TL2337). 

Amino-2-isoxazolines were prepared by the condensation of acrylonitriles with N-hydroxyurea (73BSF1138) or of urea and acetophenones, as shown in Scheme 127 (78ZOR2000). 

A number of other syntheses were discussed by Takeuchi and Furusaki and the most common involved reaction of hydroxylamine with selected a,/3-unsaturated ketones to give isoxazolidine-3- or -5-ols, which exist in equilibrium with an open-chain counterpart (77AHC(21)207). A similar equilibrium was observed in the reaction of a,/3-unsaturated ketones with N-hydroxyurea. The geometric orientation of the ring substituents was studied as a dynamic process (Scheme 158) (75TL2337). 

N-Hydroxyurea and acrylic esters produce 3-isoxazolidinones (equation 57) (76BSF1589). Phenylhydroxylamines react with diketene to provide 5-hydroxyisoxazolidones (80JHC727) which can be dehydrated to the corresponding 4-isoxazolin-3-ones (Scheme 160). 

SPECTROPHOTOMETRIC DETERMINATION OF HYDROXYUREA AS A COMPLEX WITH FERRIC CHLORIDE AFTER STABILIZATION BY FERROUS IONS... 

A simple spectrophotometric procedure for the determination of hydroxyurea (HU) has been developed. This procedure is based on the complex formation between HU and FeCl. The violet colored complex between HU and FeCl 560 nm) was not sufficiently stable to allow... 

Harmon RE., Dabrowiak JC., Brown DJ., Gupta SK., Herbert M., and Chitharanjan D. Metal Complexes of 1-Substituted 3-Hydroxyureas. Journal of Medicinal Chemistry, 1970, 13(3), 577-579. 

Hydroxyurea [127-07-1] M 76.1, m 70-72 (unstable form), m 133-136°, 141 (stable form), pK 10.6. Recrystallise from absolute EtOH (lOg in 150mL). Note that the rate of solution in boiling EtOH is slow (15-30 min). It should be stored in a cool dry place but some decomposition could occur after several weeks. lOrg Synth Coll Vol V 645 1973.] It is very soluble in H2O and can be crystd from Et20. [Acta Chem Scand 10 256 1956.]... 

The dry residue is extracted by boiling with 100 ml. of absolute ethanol, and the solution is filtered through a heated funnel. On cooling, a first crop (6-8 g.) of hydroxyurea crystallizes. 

The saline residue on the filter is extracted once again with 50 ml. of boiling absolute ethanol. On concentrating the filtrate from the second extraction and the mother liquor from the first crystallizate to a small volume, a second crop (4-6 g.) of product is obtained. The yield of the hydroxyurea is 10-14 g. (53-73%) of white crystals, m.p. 137-141° (dec.). 

Neutralization to phenolphthalein is satisfactory, but a glass electrode might give better results. Hydroxyurea is decomposed very rapidly in aqueous acidic medium, whereas its metallic salts (sodium or the copper complex salts) are stable. 

The improved method herein described is adapted from the procedure of Runti and Deghenghi. Hydroxyurea has been prepared from potassium cyanate and hydroxylamine hydrochloride. A lower melting isomeric substance, m.p. 71°, has been described." " The structure NH2CO2NH2 has been proposed for this low-melting substance. 

In addition to direct effects of chemical compounds on the fetus, metabolic disturbances in the mother, such as diabetes or hyperthermia, or deficiencies of calories or specific nutrients such as vitamin A, zinc, and folic acid may lead to teratogenesis. Compounds that inhibit placental functions may also induce malformations, e.g., by inhibiting placental circulation. For example, hydroxyurea disrupts the placental circulation and induces malformations. In addition, it also induces DNA damage. 

The mechanism of action of this unrelated group of drag is not entirely clear. Examples of miscellaneous antineoplastics include cisplatin (Platinol) and hydroxyurea (Hydrea). 

There is an increased risk for bone marrow suppression when levamisole or hydroxyurea are administered witii other antineoplastic dni. Use of levamisole witii phenytoin increases die risk of phenytoin toxicity. Pegaspargase may alter drug response of the anticoagulants. When procarbazine is administered with other central nervous system (CNS) depressants, such as alcohol, antidepressants, antihistamines, opiates, or the sedatives, an additive CNS effect may be seen. Procarbazine may potentiate hypoglycemia when administered witii insulin or oral antidiabetic dru . ... 

Ethyl carbamate, reaction with hydrox-ylamine to form hydroxyurea, 40, 60... 

Moore RD, Wong WM et al (2000) Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS 14(3) 273-278... 

Gastric mucosal injury induced by non-steroidal antiinflammatory drugs such as aspirin and indomethacin has also been extensively studied, again with somewhat conflicting results. Several studies have shown a protective effect of SOD, catalase, hydroxyurea and desferrioxamine (Takeuchi et al., 1991a Vaananen et al., 1991 Naito et al., 1992). Del Soldato etal. (1985) also found aminopy-rine, thiourea and its derivative, MK 447, and SAZ to be protective. Allopurinol has been shown to be both protective (Takeuchi etal., 1991a) and ineffective (Vaananen etal., 1991). 

Payne, A.N., Jackson, W.P., Salmon, J.A., Nicholls, A., Yeadon, M. and Garland, L.G. (1991). Hydroxamic acids and hydroxyureas as novel, selective 5-lipoxygenase inhibitors for possible use in asthma. Agents Actions 34, 189-199. 

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