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

The chemical mechanism of inhibition of Thymidylate synthetase by

5-fluorouracil is shown in Scheme 2. This process clearly shows that

in order to inactivate the TS enzyme, both 5-FU and the

tetrahydrofolate species are required to form the ternary complex.

Some clinical studies have shown that administration of a

tetrahydrofolate source prior to treatment with 5-FU results in greater

inhibition of total TS activity. The administered source of active 5,10-

methylenetetrahydrofolate is leucovorin, N-5-formyltetrahydrofolate.

TS is the most obvious and well-documented mechanism of action for

5-FU cytotoxic activity. However, other mechanisms may play a role

in the overall value of this drug in the treatment of human cancer. The

triphosphate of 5-FU nucleotide is a substrate for RNA polymerases,

and 5-FU is incorporated into the RNA of some cell lines. The

incorporation of 5-FU into DNA via DNA polymerase occurs in some

tissue lines even though uracil is not a common component of human

DNA. The 5-FU in DNA likely serves as substrate for the editing and

repair enzymes involved in DNA processing for cell division and

tissue growth. The actual addition of 5-FU into RNA and/or DNA may

not be the direct cytotoxic event, but the incorporation may lead to

less efficient utilization of cellular resources. The significance of these

various mechanisms on the overall cytotoxic effects of 5-FU may vary

with cell line and tissue.

The ####bolic activation (anabolism) of 5-FU required to

produce the anticancer effects accounts for no more than 20% of the

administered amount of drug in most patients. Catabolic inactivation

via the normal pathways for uracil consumes the remaining

approximate 80% of the dose. The major enzyme of pyrimidine

catabolism is dihydropyrimidine dehydrogenase (DPD), and 5-FU is a

substrate for this enzyme. The DPD catabolism of 5-FU is shown in

Scheme. The formation of dihydro-5-FU (5-FU-H2) occurs very

rapidly and accounts for the majority of the total 5-FU dose in most

patients. Thus, _-fluoro-_-alanine is the major human ####bolite of 5-

FU. Uracil is a substrate for this enzyme system also and has been

dosed with 5-FU and 5-FU prodrugs in an attempt to saturate DPD

and conserve active drug species. Variability in the levels of DPD

activity among the patient population is a major factor in the

bioavailability of 5-FU. Inhibitors of DPD such as uracil or 5-chloro-

2,4- dihydroxypyridine (CDHP) increase the plasma concentration–

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time curve of 5-FU by preventing 5-FU catabolism. One mechanism

of drug resistance in 5-FU–treated patients may be caused by

increased levels of DPD in the target tissue. The observed low

bioavailability of 5-FU as a result of the catabolic efficiency of DPD

and other enzymes has led to the development of unique dosing

routes and schedules as well as the development of prodrug forms of

5-FU. Attempts at chemical modification of 5-FU to protect from

catabolic events have produced several prodrug forms, which are

converted via in vivo ####bolic and/or chemical transformation to the

parent drug 5-FU. The carbamate derivative of 5_-deoxy-5-

fluorocytidine is known as capecitabine, and it is converted to 5-FU

through a series of activation steps. The activation sequence is

shown in Scheme3. The initial step is carbamate hydrolysis followed

by deamination, then hydrolysis of the sugar moiety to yield 5-FU.

Some of these activation steps take place at a higher rate in tumor

tissue leading to selective accumulation in those cells. The last step

in the sequence is catalyzed by phosphorolases, and these enzymes

occur in higher levels in colorectal tumors. Despite this complex

activation process, capecitabine still exhibits some of the significant

toxicities of 5-fluorouracil. The tetrahydrofuran derivative tegafur is

slowly converted to 5-FU but requires quite high doses to reach

therapeutic plasma concentrations. Esters of the N-hydroxymethyl

derivative of tegafur show greater anticancer activity than tegafur.

Pyrimidine analogs as anti####bolites for cancer therapy have been

developed based on the cytosine structure as well. Modification of the

normal ribose or deoxyribose moiety has produced useful drug

species such as cytarabine (ara-C) and gemcitabine, Cytosine

arabinoside (ara-C or cytarabine) is simply the arabinose sugar

instead of ribose, and the only difference in structure is the epimeric

hydroxyl group at the 2_-position of the pentose sugar. This epimeric

sugar is similar enough to the natural ribose to allow ara-C to be

incorporated into DNA, and its mechanism of action may include a

slowing of the DNA chain elongation reaction via DNA polymerase or

cellular inefficiencies in DNA processing or repair after incorporation.

Gemcitabine is the result of fluorination of the 2_-position of the sugar

moiety. Gemcitabine is the 2_,2_-difluoro deoxycytidine species and

after its anabolism to diphosphate and triphosphate ####bolites, it

inhibits ribonucleotide reductase and competes with 2_-deoxycytidine

triphosphate for incorporation into DNA. The mechanism of action for

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gemcitabine is likely similar to that of ara-C including alteration of the

rate of incorporation into DNA as well as the rate of DNA processing

and repair. Modification of the pyrimidine ring has also been explored

for the development of potential anticancer drugs based on

anti####bolite theory. Several pyrimidine nucleoside analogs have

one more or one less nitrogen in the heterocyclic ring. They are

known as azapyrimidine or deazapyrimidine nucleosides. 5-

Azacytidine is an example of a drug in this category (see Fig. 3). This

compound was developed via organic synthesis and later found as a

natural product of fungal ####bolism. The mode of action of this

compound is complex involving reversible inhibition of DNA

methyltransferase, and this lack of methylated DNA activates tumor

suppressor genes. In certain tumor systems, it is incorporated into

nucleic acids, which may result in misreading or processing errors.

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What is 5-flourouracil؟

fluoro-1H, 3H -pyrimidine-2, 4-dione

This chemical product has wourld wide trade marks drugs as fellow:-

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5-FLUOROURACIL (5-FU, EFUDEX, ADRUCIL,

FLUOROPLEX)

The drug is available in a 500-mg or 10-mL vial for IV use and

as a 1% and 5% topical cream. 5-FU is used in the treatment of

several carcinoma types including breast cancer, colorectal cancer,

stomach cancer, pancreatic cancer, and topical use in basal cell

cancer of the skin. The mechanism of action includes inhibition of the

enzyme TS by the deoxyribose monophosphate ####bolite, 5-

FdUMP. The triphosphate ####bolite is incorporated into DNA and

the ribose triphosphate into RNA. These incorporations into growing

chains result in inhibition of synthesis and function of DNA and RNA.

Resistance can occur as a result of increased expression of TS,

decreased levels of reduced folate substrate 5,10

methylenetetrahydrofolate, or increased levels of dihydropyrimidine

dehydrogenase. Dihydropyrimidine dehydrogenase is the main

enzyme responsible for 5-FU catabolism. Bioavailability following oral

absorption is erratic. Administration of 5-FU by IV yields high drug

concentrations in bone marrow and liver. The drug does distribute

into the central nervous system (CNS). Significant drug interactions

include enhanced toxicity and antitumor activity of 5-FU following

pretreatment with leucovorin. Toxicities include dose-limiting

myelosuppression, mucositis, diarrhea, and hand–foot syndrome

(numbness, pain, erythema, dryness, rash, swelling, increased

pigmentation, nail changes, pruritus of the hands and feet).

CAPECITABINE (XELODA)

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