Synthesis of Uracil and its Derivatives’ for Anticancer and Antiviral Drugs PREPARED BY ME \ ALI Yo

liver. Only about 15% is excreted unchanged. Because AZT is an

aliphatic azide, it is heat and light sensitive. It should be protected

from light and stored at 15°C to 25°C.

Zalcitabine

Zalcitabine, 2_ 3_-dideoxycytidine or ddCyd,

Is an analog of cytosine that demonstrates activity against HIV-1 and

HIV-2, including strains resistant to AZT. The potency (in peripheral

blood mononuclear cells) is similar to that of AZT, but the drug is

more active in populations of monocytes and macrophages as well as

in resting cells. Zalcitabine enters human cells by carrier-facilitated

diffusion and undergoes initial phosphorylation by deoxycytidine

kinase. The monophosphorylated compound is further ####bolized to

the active ####bolite, dideoxycytidine-5_- triphosphate (ddCTP), by

cellular kinases. ddCTP inhibits RT by competitive inhibition with

dCTP. Most likely, ddCTP causes termination of the elongating viral

DNA chain. Zalcitabine inhibits host mitochondrial DNA synthesis at

low concentrations. This effect may contribute to its clinical toxicity.

The oral bioavailability of Zalcitabine is over 80% in adults and less in

children. The major dose-limiting side effect is peripheral neuropathy,

characterized by pain, paresthesias, and hypesthesia, beginning in

the distal lower extremities. These side effects are typically evident

after several months of therapy with Zalcitabine. A potentially fatal

pancreatitis is another toxic effect of treatment with ddC. The drug

has been approved for the treatment of HIV infection in adults with

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advanced disease who are intolerant to AZT or who have disease

progression while receiving AZT. ddC is combined with AZT for the

treatment of advanced HIV infection.

Stavudine

2_3_-didehydro-2_-deoxythymidine (D4T, Zerit) .

It’s an unsaturated pyrimidine nucleoside that is related to thymidine

The drug inhibits the replication of HIV by a mechanism similar to that

of its close congener AZT. Stavudine is bio activated by cellular

enzymes to a triphosphate. The triphosphate competitively inhibits

the incorporation of thymidine triphosphate (TTP) into retroviral DNA

by RT. Stavudine also causes termination of viral DNA elongation

through its incorporation into DNA. Stavudine is available as capsules

for oral administration. The drug is acid stable and well absorbed

(about 90%) following oral administration. Stavudine has a short halflife

(1–2 hours) in plasma and is excreted largely unchanged (85%–

90%) in the urine. As with ddC, the primary dose limiting effect is

peripheral neuropathy. At the recommended dosages, approximately

15% to 20% of patients experience symptoms of peripheral

neuropathy. Stavudine is recommended for the treatment of adults

with advanced HIV infection who are intolerant of other approved

therapies or who have experienced clinical or immunological

deterioration while receiving these therapies.

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Synthesis of uracil and 5-uracil

There are five worldwide methods since 1901 to produce Uracil and

5-uracil but unfortunately no one had used in Sudan

Fischer and Roeder’s Synthesis:

The first successful laboratory synthesis of uracil was achieved

by Fischer and Roeder in 1901. Their synthesis involved the

condensation of urea and ethyl acrylate into dihydrouracil, followed by

bromination and debromination with alkali . Unfortunately, Fischer

and Roeder’s synthesis of uracils generally results in low yields.

Wheeler and Liddle’s Synthesis:

In Wheeler and Liddle’s synthesis, urea or thiourea is reacted

with a ketoester. When thiourea is used, the resulting sulfurcontaining

product must be subsequently heated in aqueous acid to

afford the desired uracil

Wheeler and Liddle’s synthesis is moderately yielding and quite

versatile, making it one of the more commonly used techniques for

the synthesis of uracils.

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Davidson-Baudisch Synthesis:

The Davidson-Baudisch synthesis of uracil is a simple one-pot

method involving the treatment of urea and malic acid with fuming

sulfuric acid:

The Davidson-Baudisch synthesis is facile and can afford various

uracils in moderate yields.

Bergmann Synthesis:

In the Bergmann synthesis, a substituted cyanoacetic acid is

condensed with urea in the presence of acetic anhydride and

subsequently reduced by catalytic hydrogenation. Reactions of this

type generally proceed in moderate yield and, unlike many of the

aforementioned syntheses, do not require harsh conditions or the

removal of sulfur.

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