5-Methyluridine 1463-10-1

The chemical compound 5-methyluridine, also called ribothymidine, is a pyrimidine nucleoside. It is the ribonucleoside counterpart to thedeoxyribonucleoside thymidine, which lacks a hydroxyl group at the 2′ position. 5-Methyluridine contains a thymine base joined to a ribosepentose sugar.

It exists in solid form as small white crystals or white crystalline powder, has a molecular weight of 258.23 u, and has a melting point of 185 °C. The stability of 5-methyluridine under standard temperature and pressure (STP) is very high.

5-Methyluridine
Identifiers
CAS number 1463-10-1 
PubChem 445408
ChemSpider 1363755 Yes
Jmol-3D images Image 1
Properties
Molecular formula C10H14N2O6
Molar mass 258.23 g/mol
Melting point 185 °C, 458 K, 365 °F

Idoxuridine 54-42-2

Idoxuridine is an anti-herpesvirus antiviral drug.

It is a nucleoside analogue, a modified form of deoxyuridine, similar enough to be incorporated into viral DNA replication, but the iodine atom added to the uracil component blocks base pairing. It is used only topically due to cardiotoxicity. It was synthesized by William Prusoff in the late 1950s.[1]

Systematic (IUPAC) name
1-[(2R,4S,5R)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-5-iodo-1,2,3,4-tetrahydropyrimidine-2,4-dione
Clinical data
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a601062
Pregnancy cat.  ?
Legal status  ?
Routes intravenously
Identifiers
CAS number 54-42-2 Yes
ATC code D06BB01 J05AB02,S01AD01
PubChem CID 5905
DrugBank DB00249
ChemSpider 10481938 Yes
UNII LGP81V5245 Yes
KEGG D00342 Yes
ChEMBL CHEMBL788 
NIAID ChemDB 001857
Synonyms Iododeoxyuridine; IUdR
Chemical data
Formula C9H11IN2O5 
Mol. mass 354.099 g/mol

Clinical use

Idoxuridine is mainly used topically to treat herpes simplex keratitis.[2] Epithelial lesions, especially initial attacks presenting with a dendritic ulcer, are most responsive to therapy, while infection with stromal involvement are less responsive.[3] Idoxuridine is ineffective against herpes simplex virus type 2 and varicella-zoster.[2]

Formulations and dosage

Idoxuridine is available as either a 0.5% ophthalmic ointment or as a 0.1% ophthalmic solution.[2] The dosage of the ointment is every 4 hours during day and once before bedtime.[2] The dosage of the solution is 1 drop in the conjunctival sac hourly during the day and every 2 hours during the night until definitive improvement, then 1 drop every 2 hours during the day and every 4 hours during the night.[2] Therapy is continued for 3-4 days after healing is complete, as demonstrated by fluorescein staining

Side effects

Common side effects of the eye drops include irritation, blurred vision and photophobia.[4] Corneal clouding and damage of the corneal epithelium may also occur.[citation needed]

5-Fluorowillardiine

5-Fluorowillardiine is a selective agonist for the AMPA receptor,[1][2][3] with only limited effects at the kainate receptor.[4] It is an excitotoxicneurotoxin when used in vivo and so is rarely used in intact animals, but it is widely used to selectively stimulate AMPA receptors in vitro.[5][6][7]

5-Fluorowillardiine exists as two distinct isomers:

5-Fluorowillardiine
Identifiers
CAS number 140187-23-1 (S) 
PubChem 1299, 126569 (S)
ChemSpider 1259 Yes, 112461 (S) Yes
DrugBank DB02966
MeSH 5-Fluorowillardiine
ChEBI CHEBI:42549 
ChEMBL CHEMBL123132 
Jmol-3D images Image 1
Properties
Molecular formula C7H8FN3O4
Molar mass 217.15 g mol−1
log P -1.168
Acidity (pKa) 2.118
Basicity (pKb) 11.879
Isoelectric point 4.28
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

Fluorouracil 51-21-8

Fluorouracil or 5-FU (trademarked as Efudex) is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitorand works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites.

Systematic (IUPAC) name
5-fluoro-1H,3H-pyrimidine-2,4-dione
Clinical data
Trade names Efudex
AHFS/Drugs.com monograph
MedlinePlus a682708
Pregnancy cat. (AU)
D (intravenous), X (topical) (US)
Legal status -only (US)
Routes Intravenous (infusion orbolus) and topical
Pharmacokinetic data
Bioavailability 28 to 100%
Protein binding 8 to 12%
Metabolism Intracellular and hepatic(CYP-mediated)
Half-life 10 to 20 minutes
Excretion Renal
Identifiers
CAS number 51-21-8 Yes
ATC code L01BC02
PubChem CID 3385
DrugBank DB00544
ChemSpider 3268 Yes
UNII U3P01618RT Yes
KEGG D00584 Yes
ChEBI CHEBI:46345 Yes
ChEMBL CHEMBL185 Yes
Chemical data
Formula C4H3FN2O2 
Mol. mass 130.077 g/mol
Physical data
Melt. point 282 – 283 °C (-195 °F)

Uses

The chemotherapy agent 5-FU, which has been used against cancer for about 40 years, acts in several ways, but principally as a thymidylate synthase inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidine, which is a nucleoside required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) into thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death.[1]

Like many anti-cancer drugs, 5-FU’s effects are felt system wide but fall most heavily upon rapidly dividing cells that make heavy use of their nucleotide synthesis machinery, such as cancer cells, but also other cells in parts of the body that are rapidly dividing, for example, the cells lining the digestive tract.

Some of its principal uses are in colorectal cancer, and pancreatic cancer, in which it has been the established form of chemotherapy for decades (platinum-containing drugs approved for human use in the US since 1978 are also very well established). It is sometimes used in the treatment of inflammatory breast cancer, an especially aggressive form of breast cancer.

5-FU is used in ophthalmic surgery, specifically to augment trabeculectomy (an operation performed to lower the intraocular pressure in patients with glaucoma) in patients deemed to be at high risk for failure. 5-FU acts as an anti-scarring agent in this regard, since excessive scarring at the trabeculectomy site is the main cause for failure of the surgery.

Fluorouracil can be used topically (as a cream) for treating actinic (solar) keratoses and some types of basal cell carcinomas of the skin. It is often referred to by its trade names EfudexCarac or Fluoroplex.

Due to fluorouracil’s toxicity and the fact that it can be manufactured using the same reaction as uracil, its precursor, 5-fluoroorotic acid, is commonly used in laboratories to screen against organisms capable of synthesizing uracil.

It is a key component in tegafur-uracil.

Synthesis

5-FU was designed, synthesized and patented by Charles Heidelberger in 1957.[2][3]

Since uracil is a normal component of RNA, the rationale behind the development of the drug was that cancer cells, with their increased genetic instability, might be more sensitive to ‘decoy’ molecules that mimic the natural compound than normal cells. The scientific goal in this case was to synthesize a drug which demonstrated specific uracil antagonism. The drug proved to have anti-tumor capabilities.

When elemental fluorine is reacted with uracil, 5-fluorouracil is produced. 5-Fluorouracil masquerades as uracil during the nucleic acid replication process. Because 5-fluorouracil is similar in shape to but does not perform the same chemistry as uracil, the drug inhibits RNA replication enzymes, thereby eliminating RNA synthesis and stopping the growth of cancerous cells.

Mode of action

As a pyrimidine analogue, it is transformed inside the cell into different cytotoxic metabolites which are then incorporated into DNA and RNA, finally inducing cell cycle arrest and apoptosis by inhibiting the cell’s ability to synthesize DNA. It is an S-phase specific drug and only active during certain cell cycles. In addition to being incorporated in DNA and RNA, the drug has been shown to inhibit the activity of the exosome complex, an exoribonuclease complex of which the activity is essential for cell survival.

Capecitabine is a prodrug that is converted into 5-FU in the tissues. It can be administered orally.

Adverse effects

Side effects include myelosuppression, mucositis, dermatitis and diarrhea.

5-FU injection and topical even in small doses cause both acute central nervous system (CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths.[4]

When using a pyrimidine-based drug, users must be aware that some people have a genetic inability to metabolize them. Current theory points to nearly 8% of the population havingdihydropyrimidine dehydrogenase (DPD) deficiency. There are laboratory tests to determine the relative activity of the DPD enzyme. It is expected that with a potential 500,000 people in North America using the pyrimidine-based 5-FU, this form of testing will increase.

The typical starting dose of capecitabine is 2,500 mg/m2 per day in Europe and 2,000 mg/m2 per day in the US. Probably the main action of 5-FU occurs when a 5-FU metabolite binds to thymidylate synthase. This binding is stable only in the presence of methylenetetrahydrofolate. It is speculated that this may explain why people in the US—a country that mandates adding folic acid to some foods—apparently require a lower dose of capecitabine than people in Europe, where countries do not mandate added folic acid.[5][6]

The body converts both folic acid and leucovorin to methylenetetrahydrofolate. Each of those precursors amplified the effect of 5-FU in one animal study.[7] However, another animal study seemed to indicate that, given the same 5-FU treatment, a special diet containing no folic acid worked better than the normal diet.[8]

Folic acid may amplify the desired action and the toxicity of 5-FU. The exact mechanism of interaction is unknown.[9]

When 5-FU is given intravenously, it is typically mixed with leucovorin in order to increase 5-FU activity. Folic acid may work as well as leucovorin, but the one human study performed (with a high dose of folic acid, from 40 mg/m2 to 140 mg/m2) had disappointing results and concluded that further studies were needed.[10] There is some confusion about whether the amount of folic acid in a normal diet and multivitamins is enough to interact badly with 5-FU.[11]

One study showed that 79 percent of the patients who switched from 5-FU (with leucovorin) to Xeloda (capecitabine) had serious side effects. None of the patients who switched from Xeloda to 5-FU (with leucovorin) had serious side effects. The researchers were unsure why.[12]

Trissel and colleagues have shown that 5-FU and leucovorin are physically incompatible when mixed in portable-pump reservoirs.[13] Similarly, infusion of 5-FU and leucovorin via permanent indwelling catheters is complicated by catheter blockage due to calcium carbonate formation (Ardalan and Flores, 1995).[14]

DPD deficiency, a pharmacogenetic syndrome leading to partial or total loss of ability to detoxify 5-FU in the liver, is strongly associated with increased risk of severe/lethal toxicities with 5-FU or oral 5-FU.[15]

[edit]History

In 1954 Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than normal liver cells. Charles Heidelberger, who had earlier found that fluorine influoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffman-La Roche to synthesize fluorouracil.[16] Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice.[17] The original 1957 report in Nature has Heidelberger as lead author, along with N.K.Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R.J. Schnitzer, E. Pleven, and J. Scheiner.[18]

[edit]Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [19]

[[File:

Fluoropyrimidine_Activity_WP1601

Fialuridine 69123-98-4

69123-98-4

Fialuridine, or 1-(2-deoxy-2-fluoro-1-D-arabinofuranosyl)-5-iodouracil (FIAU), is a nucleoside analogue. It was originally designed as a therapy forhepatitis B virus infection. Unexpected toxicity led to the death of 5 out of 15 patients in a clinical study at the NIH from fulminant liver failure. This toxicity was unusual in that it was not predicted by animal studies.

 

Fialuridine
Skeletal formula
Ball-and-stick model
Systematic (IUPAC) name
1-[(2R,3S,4R,5R)-3-Fluoro-4-hydroxy-5-(hydroxymethyl)- 2-tetrahydrofuranyl]-5-iodopyrimidine-2,4-dione
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
ATC code None
PubChem CID 50313
UNII 53T7IN77LC Yes
KEGG D04181 Yes
ChEMBL CHEMBL271475 
NIAID ChemDB 070971
Synonyms 2′-Fluoro-5-iodouracil
Chemical data
Formula C9H10FIN2O5 
Mol. mass 372.09 g/mol

Festinavir

Festinavir is an investigational new drug being developed by Bristol Myers-Squibb for the treatment of HIV infection. Festinavir is a nucleoside reverse transcriptase inhibitor that is active against HIV resistant to both abacavir and tenofovir, making the drug a candidate for people with multi-drug resistant (MDR) strains of the virus. Festinavir is a derivative of stavudine (d4T), but is less toxic.[citation needed] It was originally developed at Yale University.

Systematic (IUPAC) name
1-[(2R,5R)-5-ethynyl-5-(hydroxymethyl)-2H-furan-2-yl]-5-methylpyrimidine-2,4-dione
Clinical data
Pregnancy cat.  ?
Legal status Investigational
Identifiers
ATC code None
PubChem CID 3008897
ChemSpider 2278330
ChEMBL CHEMBL124363
NIAID ChemDB 209894
Synonyms 4′-ethynylstavudine
Chemical data
Formula C12H12N2O4 
Mol. mass 248.235 g/mol

5-Ethynyl-2′-deoxyuridine 61135-33-9

5-Ethynyl-2´-deoxyuridine (EdU) is a novel thymidine analogue, that is incorporated into dividing cells. At high doses it can be cytotoxic.

Detection

EdU is detected with a fluorescent azide which forms a covalent bond using click chemistry.[1][2] Unlike the commonly used bromodeoxyuridine, EdU detection requires no heat or acid treatment.

5-Ethynyl-2′-deoxyuridine
Identifiers
Abbreviations EdU
CAS number 61135-33-9
PubChem 472172
ChemSpider 414657
MeSH 5-ethynyl-2′-deoxyuridine
ChEMBL CHEMBL222932
Jmol-3D images Image 1
Properties
Molecular formula C11H12N2O5
Molar mass 252.22 g mol−1

Emivirine 149950-60-7

Emivirine is a failed experimental agent for the treatment of HIV. It is a non-nucleoside reverse transcriptase inhibitor.

Emivirine
Identifiers
CAS number 149950-60-7 Yes
PubChem 65013
ChemSpider 58529 
ChEMBL CHEMBL35033 
Jmol-3D images Image 1
Properties
Molecular formula C17H22N2O3
Molar mass 302.36818
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Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)

Edoxudine 15176-29-1

Edoxudine (or edoxudin) is an Antiviral drug. It is an analog of thymidine, a nucleoside.

It has shown effectiveness against herpes simplex virus.[1]

Synthesis

Edoxudine synthesis.png

Bergstrom, Donald E.; Ruth, Jerry L. (1976). “Synthesis of C-5 substituted pyrimidine nucleosides via organopalladium intermediates”. Journal of the American Chemical Society 98 (6): 1587–9. doi:10.1021/ja00422a056. PMID 1249369.

Edoxudine
Systematic (IUPAC) name
5-ethyl-1-[4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidine-2,4-dione
Clinical data
Pregnancy cat.  ?
Legal status  ?
Identifiers
CAS number 15176-29-1 Yes
ATC code D06BB09
PubChem CID 66377
ChemSpider 59752
UNII 15ZQM81Y3R Yes
Chemical data
Formula C11H16N2O5
Mol. mass 256.25514

Diucifon 34941-71-4

Diucifon is a leprostatic agent.

Identifiers
CAS number 34941-71-4
PubChem 122139
MeSH Diucifon
Jmol-3D images Image 1
Properties
Molecular formula C22H20N6O10S3
Molar mass 624.62 g mol−1