O'Really?

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].

GO ChEBI!

References

  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

4 Comments »

  1. Duncan..have you had a chance to take a look at the ChEMBL download set from their FTP site. I downloaded it to take a look at the data prior to depositing to ChemSPider and linking back to their content. I found a few issues in regards to charge balance…lots of examples of charged counterions but neutral primary component. I’m not sure whether this is something that is intended but it’s a couple of % of the database at least.

    Comment by ChemSpiderman — November 5, 2009 @ 4:47 pm | Reply

    • Hi Antony, I’d suggest you report this to either Anne Hersey, Louisa Bellis or John Overington in the ChEMBL team…

      Comment by Duncan — November 5, 2009 @ 6:03 pm | Reply

  2. I posted a comment to the ChEMBL blog for John Overington yesterday already. I confirmed on the ChEMBL website that the charge imbalance issue is there too. Things are named as hydrochlorides but shown as chloride ions. Will send an example when I am off my iPhone

    Comment by ChemSpiderman — November 5, 2009 @ 6:54 pm | Reply

  3. Here’s an example structure on the ChEMBL database: http://www.ebi.ac.uk/chembldb/index.php/compound/inspect/1047

    I have a feeling that this might be related to using a standardizer for generating standard formats but this is pure supposition. I’ll drop an email to Anne Hersey too…I know her from her time at GSK.

    Comment by ChemSpiderman — November 5, 2009 @ 7:15 pm | Reply


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