Xanthine

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Xanthine[1]
Xanthin - Xanthine.svg
Xanthine-3D-balls.png
Names
IUPAC name
3,7-Dihydropurine-2,6-dione
Other names
1H-Purine-2,6-dione
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.653
KEGG
UNII
Properties
C5H4N4O2
Molar mass 152.11 g/mol
Appearance White solid
Melting point decomposes
1 g/ 14.5 L @ 16 °C
1 g/1.4 L @ 100 °C
Hazards
NFPA 704
Flammability code 1: Must be pre-heated before ignition can occur. Flash point over 93 °C (200 °F). E.g. canola oilHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformReactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no codeNFPA 704 four-colored diamond
1
2
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

Xanthine (/ˈzænθn/ or /ˈzænθn/; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids and in other organisms.[2] Several stimulants are derived from xanthine, including caffeine and theobromine.[3]

Xanthine is a product on the pathway of purine degradation.[2]

Xanthine is subsequently converted to uric acid by the action of the xanthine oxidase enzyme.[2]

Use and manufacturing[edit]

Xanthine is used as a drug precursor for human and animal medications, and is manufactured as a pesticide ingredient.[2]

Clinical significance[edit]

Derivatives of xanthine (known collectively as xanthines) are a group of alkaloids commonly used for their effects as mild stimulants and as bronchodilators, notably in the treatment of asthma or influenza symptoms.[2] In contrast to other, more potent stimulants like sympathomimetic amines, xanthines mainly act to oppose the actions of adenosine, and increase alertness in the central nervous system.[2]

Toxicity[edit]

Due to widespread effects, the therapeutic range of xanthine is narrow, making it merely a second-line asthma treatment. The therapeutic level is 10-20 micrograms/mL blood; signs of toxicity include tremor, nausea, nervousness, and tachycardia/arrhythmia.

Methylated xanthines (methylxanthines), which include caffeine, aminophylline, IBMX, paraxanthine, pentoxifylline, theobromine, and theophylline, affect not only the airways but stimulate heart rate, force of contraction, and cardiac arrhythmias at high concentrations.[2] In high doses, they can lead to convulsions that are resistant to anticonvulsants.[2] Methylxanthines induce acid and pepsin secretions in the gastrointestinal tract.[2] Methylxanthines are metabolized by cytochrome P450 in the liver.[2]

If swallowed, inhaled, or exposed to the eyes in high amounts, xanthines can be harmful, and may cause an allergic reaction if applied topically.[2]

Pharmacology[edit]

In in vitro pharmacological studies, xanthines act as both:

  1. competitive nonselective phosphodiesterase inhibitors which raise intracellular cAMP, activate PKA, inhibit TNF-α[2][4] and leukotriene[5] synthesis, and reduce inflammation and innate immunity[5] and
  2. nonselective adenosine receptor antagonists [6] which inhibit sleepiness-inducing adenosine.[2]

But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthines (some nonmethylated) have been developed searching for compounds with greater selectivity for phosphodiesterase enzyme or adenosine receptor subtypes.[2][7][8][9][10][11]

Xanthine: R1 = R2 = R3 = H
Caffeine: R1 = R2 = R3 = CH3
Theobromine: R1 = H, R2 = R3 = CH3
Theophylline: R1 = R2 = CH3, R3 = H
Examples of xanthine derivatives
Name R1 R2 R3 R8 IUPAC nomenclature Found in
Xanthine H H H H 3,7-Dihydro-purine-2,6-dione Plants, animals
Caffeine CH3 CH3 CH3 H 1,3,7-Trimethyl-1H-purine-2,6(3H,7H)-dione Coffee, guarana, yerba mate, tea, kola, guayusa, holly
Theobromine H CH3 CH3 H 3,7-Dihydro-3,7-dimethyl-1H-purine-2,6-dione Cacao (chocolate), yerba mate, kola, guayusa, holly
Theophylline CH3 CH3 H H 1,3-Dimethyl-7H-purine-2,6-dione Tea, cacao (chocolate), yerba mate, kola
Paraxanthine CH3 H CH3 H 1,7-Dimethyl-7H-purine-2,6-dione Animals that have consumed caffeine
8-Chlorotheophylline CH3 CH3 H Cl 8-Chloro-1,3-dimethyl-7H-purine-2,6-dione Synthetic pharmaceutical ingredient
Diprophylline CH3 CH3 C3H7O2 H 7-(2,3-Dihydroxypropyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione Synthetic pharmaceutical ingredient
IBMX CH3 C4H9 H H 1-Methyl-3-(2-methylpropyl)-7H-purine-2,6-dione
Uric acid H H H O 7,9-Dihydro-1H-purine-2,6,8(3H)-trione Byproduct of purine nucleotides metabolism and a normal component of urine

Pathology[edit]

People with the rare genetic disorders, specifically xanthinuria and Lesch-Nyhan syndrome, lack sufficient xanthine oxidase and cannot convert xanthine to uric acid.[2]

Speculation on origin[edit]

Studies reported in 2008, based on 12C/13C isotopic ratios of organic compounds found in the Murchison meteorite, suggested that xanthine and related chemicals, including the RNA component uracil, were formed extraterrestrially.[12][13] In August 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting xanthine and related organic molecules, including the DNA and RNA components adenine and guanine, were found in outer space.[14][15][16]

See also[edit]

References[edit]

  1. ^ Merck Index, 11th Edition, 9968.
  2. ^ a b c d e f g h i j k l m n o "Xanthine, CID 1188". PubChem, National Library of Medicine, US National Institutes of Health. 2019. Retrieved 28 September 2019.
  3. ^ Spiller, Gene A. (1998). Caffeine. Boca Raton: CRC Press. ISBN 0-8493-2647-8.
  4. ^ Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365.
  5. ^ a b Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005). "Leukotrienes: underappreciated mediators of innate immune responses". J. Immunol. 174 (2): 589–94. doi:10.4049/jimmunol.174.2.589. PMID 15634873.
  6. ^ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Prog Clin Biol Res. 230 (1): 41–63. PMID 3588607.
  7. ^ Daly JW, Padgett WL, Shamim MT (July 1986). "Analogues of caffeine and theophylline: effect of structural alterations on affinity at adenosine receptors". Journal of Medicinal Chemistry. 29 (7): 1305–8. doi:10.1021/jm00157a035. PMID 3806581.
  8. ^ Daly JW, Jacobson KA, Ukena D (1987). "Adenosine receptors: development of selective agonists and antagonists". Progress in Clinical and Biological Research. 230: 41–63. PMID 3588607.
  9. ^ Daly JW, Hide I, Müller CE, Shamim M (1991). "Caffeine analogs: structure-activity relationships at adenosine receptors". Pharmacology. 42 (6): 309–21. doi:10.1159/000138813. PMID 1658821.
  10. ^ González MP, Terán C, Teijeira M (May 2008). "Search for new antagonist ligands for adenosine receptors from QSAR point of view. How close are we?". Medicinal Research Reviews. 28 (3): 329–71. doi:10.1002/med.20108. PMID 17668454.
  11. ^ Baraldi PG, Tabrizi MA, Gessi S, Borea PA (January 2008). "Adenosine receptor antagonists: translating medicinal chemistry and pharmacology into clinical utility". Chemical Reviews. 108 (1): 238–63. doi:10.1021/cr0682195. PMID 18181659.
  12. ^ Martins, Z.; Botta, O.; Fogel, M. L.; Sephton, M. A.; Glavin, D. P.; Watson, J. S.; Dworkin, J. P.; Schwartz, A. W.; Ehrenfreund, P. (2008). "Extraterrestrial nucleobases in the Murchison meteorite". Earth and Planetary Science Letters. 270 (1–2): 130–136. arXiv:0806.2286. Bibcode:2008E&PSL.270..130M. doi:10.1016/j.epsl.2008.03.026.
  13. ^ AFP Staff (13 June 2008). "We may all be space aliens: study". AFP. Archived from the original on June 17, 2008. Retrieved 2011-08-14.
  14. ^ Callahan, M. P.; Smith, K. E.; Cleaves, H. J.; Ruzicka, J.; Stern, J. C.; Glavin, D. P.; House, C. H.; Dworkin, J. P. (2011). "Carbonaceous meteorites contain a wide range of extraterrestrial nucleobases". Proceedings of the National Academy of Sciences. 108 (34): 13995–8. Bibcode:2011PNAS..10813995C. doi:10.1073/pnas.1106493108. PMC 3161613. PMID 21836052.
  15. ^ Steigerwald, John (8 August 2011). "NASA Researchers: DNA Building Blocks Can Be Made in Space". NASA. Retrieved 2011-08-10.
  16. ^ ScienceDaily Staff (9 August 2011). "DNA Building Blocks Can Be Made in Space, NASA Evidence Suggests". ScienceDaily. Retrieved 2011-08-09.