May 6, 2010

Mephedrone: Entity of the Month

Overdosed by Elad R, on FlickrRelease 68 of Chemical Entities of Biological Interest (ChEBI) is now available, with 549,319 total entities, of which 21,075 are fully annotated. This month’s entity of the month is Mephedrone, a substance which has been in the news headlines lately and as wikipedia points out is “not to be confused with Methedrine, Methedrone, Methadone, or Methylone“. Don’t you just love chemical names?! Text below reproduced from the ChEBI website:

“Mephedrone (CHEBI:59331) is a synthetic central nervous system stimulant and entactogen drug chemically related to cathinone, the psychoactive alkaloid present in the khat plant (Catha edulis, family Celastraceae).

It can be synthesised from 4-methylpropiophenone by an initial bromination at the β-carbon followed by replacement of the bromine by a methylamino group derived from methylamine hydrochloride. Although it was probably not available until 2007, by 2009 mephedrone had become the fourth most popular street drug in the UK, behind cannabis, cocaine and ecstasy. Little is currently known regarding its pharmacology or toxicology, although one recent report suggests the likelihood that it stimulates the release of, and then inhibits the reuptake of, monoamine neurotransmitters [1].

Although already listed as a prohibited substance in many countries, in others it has varying degrees of legality (notably the USA where it is currently unscheduled under the Controlled Substances Act). In the UK, a decision by the Home Secretary to classify mephedrone as illegal caused the resignation of two members of the Advisory Council on the Misuse of Drugs (ACMD) which has led in turn to a general questioning of UK drugs policy. Mephedrone finally became classified as a Class B drug in the UK on April 16, 2010 – prior to this time it was often sold openly under the guise of a ‘plant food’ (although having no known use as such).”


  1. Winstock, A., Marsden, J., & Mitcheson, L. (2010). What should be done about mephedrone? BMJ, 340:c1605 DOI: 10.1136/bmj.c1605

[Creative Commons licensed picture ‘Overdosed’ by Elad Rahmin on flickr]

April 8, 2010

8-OHdG: Entity of the Month

DNA Origami by Alex BatemanChemical Entities of Biological Interest (ChEBI) release 67 is now available, containing 548,850 total entities, of which 20,565 are annotated entities and 720 were submitted via the ChEBI submission tool. New in this release, the ChEBI ontology is now available in the Web Ontology Language (OWL), which is part of an ongoing research project to automate the classification of small molecules in ChEBI. If you’re using this data, we’d like to hear from you! This month’s entity of the month is 8-OHdG. Text below reproduced from ChEBI website:

8-Hydroxy-2′-deoxyguanosine (8-OHdG, ChEBI:40304) is an important molecule in oxidative stress used as a biomarker of many processes involving reactive oxygen species. Also known as 8-oxo-dG (this abbreviation derived from its tautomeric name 8-oxo-7,8-dihydro-2′-deoxyguanosine) and as HMDB03333 in the Human Metabolome Database [1], it has been used especially as a sensitive marker of the DNA damage caused by hydroxyl radical attack at C-8 of guanine. This damage, if left unrepaired, has been proposed to contribute to mutagenicity and cancer promotion [2]. This use of 8-OHdG as a biomarker for DNA damage extends over a wide range of scenarios [3,4,5,6], because it is one of the major products of DNA oxidation.

More recent work by Junko Fujihara and his colleagues at Shimane University in Japan has demonstrated how 8-OHdG can be used as a possible marker for arsenic poisoning, since antiquity a method of dispatch frequent in homicide and suicide cases [7]. Fujihara’s study however focuses principally on the use of arsenic in medicine, and specifically in demonstrating a relationship between concentrations of 8-OHdG and various arsenic compounds in the urine of a patient with acute promyelocytic leukaemia being treated with arsenic trioxide. Their conclusions that 8-OHdG in urine can be used therapeutically as a key biomarker for arsenic compounds may also find application in the diagnosis of arsenic poisoning when arising from the consumption of seafood such as fish, shrimp, oysters and seaweeds, organisms known to contain appreciable amounts of arsenic compounds.

[Picture of Alex Bateman‘s DNA origami in action from The Wellcome Trust Sanger Institute.]


  1. Wishart, D., Knox, C., Guo, A., Eisner, R., Young, N., Gautam, B., Hau, D., Psychogios, N., Dong, E., Bouatra, S., Mandal, R., Sinelnikov, I., Xia, J., Jia, L., Cruz, J., Lim, E., Sobsey, C., Shrivastava, S., Huang, P., Liu, P., Fang, L., Peng, J., Fradette, R., Cheng, D., Tzur, D., Clements, M., Lewis, A., De Souza, A., Zuniga, A., Dawe, M., Xiong, Y., Clive, D., Greiner, R., Nazyrova, A., Shaykhutdinov, R., Li, L., Vogel, H., & Forsythe, I. (2009). HMDB: a knowledgebase for the human metabolome Nucleic Acids Research, 37 (Database) DOI: 10.1093/nar/gkn810
  2. Kuchino, Y., Mori, F., Kasai, H., Inoue, H., Iwai, S., Miura, K., Ohtsuka, E., & Nishimura, S. (1987). Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues Nature, 327 (6117), 77-79 DOI: 10.1038/327077a0
  3. Wu LL, Chiou CC, Chang PY, & Wu JT (2004). Urinary 8-OHdG: a marker of oxidative stress to DNA and a risk factor for cancer, atherosclerosis and diabetics. Clinica chimica acta; international journal of clinical chemistry, 339 (1-2), 1-9 PMID: 14687888
  4. Schriner, S. (2005). Extension of Murine Life Span by Overexpression of Catalase Targeted to Mitochondria Science, 308 (5730), 1909-1911 DOI: 10.1126/science.1106653
  5. Sumida S, Doi T, Sakurai M, Yoshioka Y, & Okamura K (1997). Effect of a single bout of exercise and beta-carotene supplementation on the urinary excretion of 8-hydroxy-deoxyguanosine in humans. Free radical research, 27 (6), 607-18 PMID: 9455696
  6. Tarng DC, Huang TP, Wei YH, Liu TY, Chen HW, Wen Chen T, & Yang WC (2000). 8-hydroxy-2′-deoxyguanosine of leukocyte DNA as a marker of oxidative stress in chronic hemodialysis patients. American journal of kidney diseases : the official journal of the National Kidney Foundation, 36 (5), 934-44 PMID: 11054349
  7. Fujihara, J., Agusa, T., Tanaka, J., Fujii, Y., Moritani, T., Hasegawa, M., Iwata, H., Tanabe, S., & Takeshita, H. (2009). 8-Hydroxy-2′-deoxyguanosine (8-OHdG) as a possible marker of arsenic poisoning: a clinical case study on the relationship between concentrations of 8-OHdG and each arsenic compound in urine of an acute promyelocytic leukemia patient being treated with a Forensic Toxicology, 27 (1), 41-44 DOI: 10.1007/s11419-008-0062-x

March 4, 2010

Sildenafil citrate: Entity of the Month

30 St Mary Axe or the Gherkin - London by Patrick MayonRelease 66 of Chemical Entities of Biological Interest (ChEBI) is now available, containing 534,521 total entities, of which 20,151 are annotated entities and 698 were submitted via the ChEBI submission tool. This months entity of the month is Viagra, also known as Sildenafil citrate: (Text below reproduced from ChEBI website)

Few chemical compounds are better known to the general public than sildenafil citrate (CHEBI:58987), traded under the name of “Viagra”.The compound was first synthesised by chemists working at Pfizer, with a view to using it for the treatment of hypertension and angina pectoris. Whilst having been found to be ineffective against angina in clinical trials, it has been observed to induce penile erections and was therefore marketed by Pfizer as a drug for the treatment of erectile dysfunction.

A number of synthetic routes for the preparation of the parent sildenafil have been reported [1]. A common industrial synthetic route is through reaction of 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide and 2-ethoxy-5-(4-methylpiperazin-1-yl)sulfonylbenzoic acid followed by subsequent cyclisation to sildenafil through heating under acidic conditions.

Sildenafil has been shown to be an inhibitor of cyclic guanosine monophosphate specific phosphodiesterase type 5, an enzyme which is responsible for the degradation of 3′,5′-cyclic GMP (cyclic guanosine monophosphate, cGMP) in the corpus cavernosum. This leads to the presence of increased levels of cGMP, which, in turn causes vasodilation of the helicine arteries and thus increased blood flow into the spongy tissue of the penis [2].

Apart from the treatment of sexual dysfunction, sildenafil is also used in the treatment of pulmonary arterial hypertension and works again through relaxation of the arterial wall, which leads to a decrease in arterial resistance [3]. Furthermore – and arguably most interestingly – sildenafil has been found to decrease the time necessary for the re-entrainment of circadian rhythms after phase advances in the light–dark cycle (such as occur on transmeridian eastbound flights) in members of the Cricetidae family [4]*. The discovery was rewarded with the award of an Ig Nobel Prize in Aviation in 2007.

* or as wikipedia puts it…”Viagra aids jet lag recovery in hamsters” …that’s an interesting side effect.


  1. Dunn, P. (2005). Synthesis of Commercial Phosphodiesterase(V) Inhibitors Organic Process Research & Development, 9 (1), 88-97 DOI: 10.1021/op040019c
  2. Webb DJ, Freestone S, Allen MJ, & Muirhead GJ (1999). Sildenafil citrate and blood-pressure-lowering drugs: results of drug interaction studies with an organic nitrate and a calcium antagonist. The American journal of cardiology, 83 (5A) PMID: 10078539
  3. Richalet, J. (2004). Sildenafil Inhibits Altitude-induced Hypoxemia and Pulmonary Hypertension American Journal of Respiratory and Critical Care Medicine, 171 (3), 275-281 DOI: 10.1164/rccm.200406-804OC
  4. Agostino, P., Plano, S., & Golombek, D. (2007). Sildenafil accelerates reentrainment of circadian rhythms after advancing light schedules Proceedings of the National Academy of Sciences, 104 (23), 9834-9839 DOI: 10.1073/pnas.0703388104

[Creative Commons licensed picture of 30 St Mary Axe or the Gherkin – London by Patrick Mayon, see comments on this post at friendfeed]

January 11, 2010

Abscisic Acid: Entity of the Month

Sweetgum bud by Martin LaBarHappy New Year from the ChEBI team where release 64 is now available, containing 534,142 total entities, of which 19,645 are annotated entities and 693 were submitted via the ChEBI submission tool. This month’s entity of the month is Abscisic acid.

(+)-Abscisic acid (CHEBI:2365), known commonly just as abscisic acid or ABA, is a ubiquitous isoprenoid plant hormone which is synthesized in the methylerythritol phosphate (MEP) pathway (also known as the non-mevalonate pathway) by cleavage of C40 carotenoids.

First identified and characterised in 1963 by Fredrick Addicott and his associates at the University of California, Davis [1], ABA was originally believed to play a major role in abscission of fruits (hence its early name of ‘abscisin II’). This is now known to be true for only a small number of plants, a wider role being to act as a regulator of plant responses to a variety of environmental stresses such as drought, extremes of temperatures, and high salinity. Such responses include stimulating the closure of stomata, inhibiting shoot growth while not affecting root growth, and inducing seeds to synthesise storage proteins.

Because of its essential function in plant physiology, targeting the ABA signalling pathway holds considerable promise for future applications in agriculture. Now, in a recent issue of Nature, Ning Zheng and his co-worker Laura Sheard from the University of Washington summarise recent converging studies which reveal the details of how ABA transmits its message [2]. In particular, an article by an international team led by Eric Xu of the Van Andel Research Institute describes how their crystallographic work on unbound ABA and ABA bound to some of its receptors, together with extensive biochemical studies from elsewhere, identify a conserved gate–latch–lock mechanism underlying ABA signalling [3].


  1. Ohkuma, K., Lyon, J., Addicott, F., & Smith, O. (1963). Abscisin II, an Abscission-Accelerating Substance from Young Cotton Fruit Science, 142 (3599), 1592-1593 DOI: 10.1126/science.142.3599.1592
  2. Sheard, L., & Zheng, N. (2009). Plant biology: Signal advance for abscisic acid Nature, 462 (7273), 575-576 DOI: 10.1038/462575a
  3. Melcher, K., Ng, L., Zhou, X., Soon, F., Xu, Y., Suino-Powell, K., Park, S., Weiner, J., Fujii, H., Chinnusamy, V., Kovach, A., Li, J., Wang, Y., Li, J., Peterson, F., Jensen, D., Yong, E., Volkman, B., Cutler, S., Zhu, J., & Xu, H. (2009). A gate–latch–lock mechanism for hormone signalling by abscisic acid receptors Nature, 462 (7273), 602-608 DOI: 10.1038/nature08613

[CC-licensed picture of sweetgum bud by Martin Labar]

December 5, 2009

Adrenaline: Entity of the Month

XML Summer School, Oxford, U.K.December’s entity of the month at ChEBI is Adrenaline, for all the adrenaline junkies out there. This accompanies ChEBI release 63, containing 536,978 total entities, of which 19,501 are annotated entities and 678 were submitted via the ChEBI submission tool. Text reproduced below from the ChEBI website:

Adrenaline (CHEBI:33568), also known as epinephrine, is a catecholamine that acts as a hormone and neurotransmitter.

It was first isolated from an extract of the suprarenal (adrenal) gland as its mono-benzoyl derivative by the American biochemist and pharmacologist John Jacob Abel in 1889 [1] who later also crystallised it as a hydrate. The pure compound was produced in 1901 by the Japanese industrial chemist Jokichi Takamine [2] and patented as ‘Adrenalin’. Two chemists, Stolz and Dakin, independently reported the synthesis of the compound in 1904 [3,4].

Adrenaline is a potent ‘fight-or-flight’ hormone, which is produced in stress situations. When produced in the body, it leads to an increase in heart-rate, vasodilation and the supply of both glucose and oxygen to the muscles and the brain, thus preparing the body for rapid action if needed. The increase in glucose supply is achieved through the binding of adrenaline to β-adrenergic receptors in the liver. This triggers the adenylate cyclase pathway, which, in turn, leads to increased glycogenolysis activity. On the other hand, adrenaline suppresses both digestive processes as well as immune responses. As such, it can be used in the treatment of anaphylactic shock [5] as well as for the treatment of cardiac arrest and cardiac disrythmias [6].

The biosynthesis of adrenaline is regulated by the central nervous system. It is ultimately derived from L-tyrosine, which is converted into L-dihydroxyphenylalanine (L-DOPA) by the action of tyrosine 3-monooxygenase (EC Adrenaline is produced through the conversion of L-DOPA into dopamine into noradrenaline into adrenaline itself.


  1. Abel, J.J. (1899) Ueber den blutdruckerregenden Bestandtheil der Nebenniere, das Epinephrin. Z. Physiol. Chem. 18, 318–324.
  2. Takamine, J., (1902) The isolation of the active principle of the suprarenal gland. J. Physiol. 27 (Suppl), xxix–xxx.
  3. Stolz, F. (1904) Ueber Adrenalin und Alkylaminoacetobrenzkatechin. Ber. Dtsch. Chem. Ges. 37, 4149–4154.
  4. Dakin, H.D. (1905) The synthesis of a substance allied to noradrenaline. Proc. Roy. Soc. Lon. Ser. B 76, 491–497.
  5. ANCHOR, J. (2004). Appropriate use of epinephrine in anaphylaxis The American Journal of Emergency Medicine, 22 (6), 488-490 DOI: 10.1016/j.ajem.2004.07.016
  6. Rainer TH, & Robertson CE (1996). Adrenaline, cardiac arrest, and evidence based medicine. Journal of accident & emergency medicine, 13 (4), 234-7 PMID: 8832338

[CC licensed picture of dan wakeham pipe by jeffcapeshop]

November 5, 2009

Artemether: Entity of the Month

ArtemetherNovember’s entity of the month at ChEBI is the antimalarial drug Artemether. This accompanies release 62 of ChEBI, not just yet another incremental release but an increase of more than twentyfold in the number of entities in ChEBI, thanks to merging of data between an updated ChEBI [1] and ChEMBL [2]. ChEBI now (as of release 62) has over 455,000 total entities, compared to just under 19,000 in the previous version (release 61), see ChEBI news for details. The text below on Artemether is reproduced from the ChEBI website, where content is available under a Creative Commons license:

Artemether (CHEBI:195280) is a lipid-soluble antimalarial for the treatment of multi-drug resistant strains of Plasmodium falciparum malaria. First prepared in 1979 [3], it is a methyl ether of the naturally occurring sesquiterpene lactone (+)-artemisinin, which is isolated from the leaves of Artemisia annua L. (sweet wormwood), the traditional Chinese medicinal herb known as Qinghao. However, because of artemether’s extremely rapid mode of action (it has an elimination half-life of only 2 hours, being metabolized to dihydroartemisinin which then undergoes rapid clearance), it is used in combination with other, longer-acting, drugs. One such combination, licensed in April of this year by the WHO, is Coartem in which the artemether is mixed with lumefantrine – a racemic mixture of a synthetic fluorene derivative known formerly as benflumetol – which has a much longer and pharmacologically complementary terminal half-life of 3–6 days, allowing the two drugs to act synergistically against Plasmodium.

The molecule of artemether is interesting because of its extreme rigidity, with very few rotational bonds. Unlike quinine class antimalarial drugs, it has no nitrogen atom in its skeleton. However, an important chemical feature (and unique in drugs) is the presence of an O–O endoperoxide bridge which is essential for its antimalarial activity, as it is this bridge which is split in an interaction with heme, blocking the conversion into hemozoin and thus releasing into the parasite heme and a host of free radicals which attack the cell membrane.

Artemether is fully Rule-of-Five compliant and has recently also been under investigation as a possible candidate for cancer treatment [4,5].



  1. de Matos, P., Alcantara, R., Dekker, A., Ennis, M., Hastings, J., Haug, K., Spiteri, I., Turner, S., & Steinbeck, C. (2009). Chemical Entities of Biological Interest: an update Nucleic Acids Research DOI: 10.1093/nar/gkp886
  2. Warr, W. (2009). ChEMBL. An interview with John Overington, team leader, chemogenomics at the European Bioinformatics Institute Outstation of the European Molecular Biology Laboratory (EMBL-EBI) Journal of Computer-Aided Molecular Design, 23 (4), 195-198 DOI: 10.1007/s10822-009-9260-9
  3. Li, Y. et al. (1979) K’o Hsueh T’ung Pao, 24, 667 [Chem. Abstr., 91, 211376u].
  4. Singh, N., & Panwar, V. (2006). Case Report of a Pituitary Macroadenoma Treated With Artemether Integrative Cancer Therapies, 5 (4), 391-394 DOI: 10.1177/1534735406295311
  5. Wu, Z., Gao, C., Wu, Y., Zhu, Q., Yan Chen, ., Xin Liu, ., & Chuen Liu, . (2009). Inhibitive Effect of Artemether on Tumor Growth and Angiogenesis in the Rat C6 Orthotopic Brain Gliomas Model Integrative Cancer Therapies, 8 (1), 88-92 DOI: 10.1177/1534735408330714

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