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Chemistry
Hydroxyurea has been prepared in many different ways since its initial synthesis in 1869. Medicinal chemists, Dresler and Stein created Hydroxyurea from hydroxylamine, hydrochloric acid and potassium cyanide as a technical exercise in organic chemistry, as part of a series of experiments generating derivatives of urea. Hydroxyurea lay dormant for more than fifty years until it was studied as part of an investigation into the toxicity of protein metabolites.

One common mechanism for synthesizing hydroxyurea is by the reaction of calcium cyanate with hydroxylamine nitrate in absolute ethanol and by the reaction of salt (i.e. sodium or potassium) cyanates and hydroxylamine hydrochloride in aqueous solution. Hydroxyurea has also been prepared by converting a quaternary ammonium anion exchange resin from the chloride form to the cyanate form with sodium cyanate and reacting the resin in the cyanate form with hydroxylamine hydrochloride. This method of hydroxyurea synthesis patented by Hussain et al (2015) is shown in the diagram below.

Pharmacology
Hydroxyurea is a monohydroxyl-substituted urea (hydroxycarbamate) antimetabolite. Similar to other antimetabolite anti-cancer drugs, it acts by disrupting the DNA replication process of dividing cancer cells in the body. Hydroxyurea selectively inhibits ribonucleoside diphosphate reductase, an enzyme required to convert ribonucleoside diphosphates into deoxyribonucleoside diphosphates, thereby preventing cells from leaving the G1/S phase of the cell cycle. This agent also exhibits radiosensitizing activity by maintaining cells in the radiation-sensitive G1 phase and interfering with DNA repair.

Biochemical research has explored its role as a DNA replication inhibitor which causes deoxyribonucleotide depletion and results in DNA double strand breaks near replication forks (see DNA repair). Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea renders cells sensitive to bleomycin, an alkylating anti-tumor antibiotic, because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to the chelating properties of bleomycin, which then produces active oxygen.

Hydroxyurea has many pharmacological applications under the Medical Subject Headings (MeSH) classification system:


 * Antineoplastic Agents - Substances that inhibit or prevent the proliferation of neoplasms.
 * Antisickling Agents - Agents used to prevent or reverse the pathological events leading to sickling of erythrocytes in sickle cell conditions.
 * Nucleic Acid Synthesis Inhibitors - Compounds that inhibit cell production of DNA or RNA.
 * Enzyme Inhibitors - Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
 * Cytochrome P-450 CYP2D6 Inhibitors - Acts as an inhibitor to one of the most important enzymes involved in the metabolism of xenobiotics in the body, CYP2D6 a member of the cytochrome P450 mixed oxidase system.

Cancer treatment
Antimetabolites can be used in cancer treatment, as they interfere with DNA production and therefore cell division and tumor growth. Because cancer cells spend more time dividing than other cells, inhibiting cell division harms tumor cells more than other cells. These drugs are commonly used to treat leukemia, cancers of the breast, ovary, and the gastrointestinal tract, as well as other types of cancers. In the Anatomical Therapeutic Chemical Classification System antimetabolite cancer drugs are classified under L01B.

Antimetabolites generally impair DNA replication machinery, either by the incorporation of chemically altered nucleotides or by depleting the supply of deoxynucleotides needed for DNA replication and cell proliferation.

Examples of cancer drug antimetabolites include, but are not limited to the following:
 * 5-Fluorouracil (5-FU)
 * 6-Mercaptopurine (6-MP)
 * Capecitabine (Xeloda®)
 * Cytarabine (Ara-C®)
 * Floxuridine
 * Fludarabine
 * Gemcitabine (Gemzar®)
 * Hydroxycarbamide
 * Methotrexate
 * Pemetrexed (Alimta®)

Anti-metabolites masquerade as a purine (azathioprine, mercaptopurine) or a pyrimidine, chemicals that become the building-blocks of DNA. They prevent these substances from becoming incorporated into DNA during the S phase (of the cell cycle), stopping normal development and cell division. Anti-metabolites also affect RNA synthesis. However, because thymidine is used in DNA but not in RNA (where uracil is used instead), inhibition of thymidine synthesis via thymidylate synthase selectively inhibits DNA synthesis over RNA synthesis.

Due to their efficiency, these drugs are the most widely used cytostatics. Competition for the binding sites of enzymes that participate in essential biosynthetic processes and subsequent incorporation of these biomolecules into nucleic acids, inhibits their normal tumor cell function and triggers apoptosis, or the cell death process. Because of this mode of action, most antimetabolites have high cell cycle specificity.

Antibiotics
Antimetabolites may also be antibiotics, such as sulfanilamide drugs, which inhibit dihydrofolate synthesis in bacteria by competing with para-aminobenzoic acid (PABA). PABA is needed in enzymatic reactions that produce folic acid, which acts as a coenzyme in the synthesis of purines and pyrimidines, the building-blocks of DNA. Mammals do not synthesize their own folic acid so they are unaffected by PABA inhibitors, which selectively kill bacteria. Sulfanilamide drugs are not like the antibiotics used to treat infections. Instead, they work by changing the DNA inside cancer cells to keep them from growing and multiplying. Antitumor antibiotics are a class of antimetabolite drugs that are cell cycle nonspecific. They act by binding with DNA molecules and preventing RNA (ribonucleic acid) synthesis, a key step in the creation of proteins, which are necessary for cell survival.

Anthracyclines are anti-tumor antibiotics that interfere with enzymes involved in copying DNA during the cell cycle.

Examples of anthracyclines include:
 * Daunorubicin
 * Doxorubicin (Adriamycin®)
 * Epirubicin
 * Idarubicin

Anti-tumor antibiotics that are not anthracyclines include:


 * Actinomycin-D
 * Bleomycin
 * Mitomycin-C
 * Mitoxantrone