ChEBI Entity of the Month

29 October 2008, PP121

A pyrazolopyrimidine, known simply as PP121 (CHEBI:50915), has been found to block simultaneously two key enzymes involved in the growth of cancer cells. In a recent publication [1], Kevan Shokat, of the University of California at Berkeley, and collaborators report that PP121 is highly effective in inhibiting both oncogenic tyrosine kinases and phosphatidylinositol-3-OH kinases [PI(3)Ks], two protein families that are currently among the most intensely pursued cancer drug targets. The enzymes are involved in cell signalling pathways, alterations of which are involved in many types of cancer. This example of dual inhibition owes its effectiveness to the ability of the molecule to flex around the single bond connecting its pyrazolopyrimidine and pyrrolopyridine ring systems. Thus the molecule is able to change its shape slightly, enabling it to occupy a hydrophobic pocket in both enzyme classes. The researchers believe that the rational design approach employed by them demonstrates the possibility to identify potent, selective and drug-like molecules capable of targeting these two classes of oncogenic kinases, and in the long term to providing routes to more effective therapy for many cancers.

Reference

24 September 2008, Dronedarone

Atrial fibrillation (AF) is the most common form of cardiac arrhythmia (abnormal heart rhythm). Risk increases with age, with 8% of people over 80 having AF. Historically, the most effective treatment for this disorder has been either oral or intravenous administration of the iodinated benzofuran derivative amiodarone (CHEBI:2663), a procedure which has been used safely in patients with even advanced heart failure. However the use of amiodarone has been limited by cumulative and often irreversible organ toxicity, especially in younger patients. In an effort to provide equivalent efficacy and safety with less toxicity, dronedarone (CHEBI:50659) [2], a pharmacologically related benzofuran derivative lacking the iodine moieties, has been developed [1] and subjected to clinical trials. The U.S. Food and Drug Administration (FDA) assigned priority review status to dronedarone in August 2008 following the exciting results of the ATHENA study [3], a large randomized trial which showed a significant decreased risk of cardiovascular hospitalizations or death from any cause in patients with AF treated with dronedarone. Moreover, data presented at the European Society of Cardiology Congress in September [4] suggests that dronedarone could also reduce the risk of stroke for certain elderly patients with AF.

References

3 September 2008, Putrebactin

Siderophores are natural ferric chelators synthesised and excreted by microorganisms. Under aerobic conditions, iron exists mostly in oxidation state III (ferric) and tends to form highly insoluble minerals. Therefore, many microorganisms depend on siderophores for iron uptake. Putrebactin (CHEBI:50432) is a macrocyclic siderophore produced by the marine bacterium Shewanella putrefaciens [1]. It is derived from N-hydroxy-N-succinylputrescine (HSP) and is structurally similar to desferrioxamine E. It was recently shown that desferrioxamine siderophore synthetase DesD catalyses ATP-dependent trimerisation–macrocyclisation of N-hydroxy-N-succinylcadaverine to desferrioxamine E [2]. A BLAST similarity search identified a gene called pubC within a conserved five-gene cluster in several Shewanella species that encodes a homologue of DesD [1]. It was suggested that pubABC encodes the enzymes required to assemble putrebactin from putrescine, with PubA catalysing the dioxygen and FADH₂-dependent hydroxylation of putrescine to N-hydroxyputrescine, PubB catalysing its succinyl-CoA-dependent succinylation to HSP, and PubC catalysing ATP-dependent dimerisation of HSP to give pre-putrebactin and its subsequent macrocyclisation to putrebactin. The pubA, pubB and pubC genes are homologous to the alcA, alcB and alcC genes, respectively, which are involved in the biosynthesis of alcaligin, a dihydroxylated analogue of putrebactin isolated from Bordetella species [3].

References

30 July 2008, 3,3'-Diindolylmethane

3,3'-Diindolylmethane (DIM; CHEBI:50182) is a lipophilic oil-soluble natural product derived from the autolysis of glucobrassicin, a compound present in food plants of the Brassica genus, including broccoli, cabbage, Brussels sprouts and cauliflower. The autolytic reaction requires the enzyme thioglucosidase (EC 3.2.1.147) which is endogenous to these plants and released upon rupture of the cell wall. 3,3'-Diindolylmethane shows several biological properties such as potent antiproliferative and antiandrogenic effects [1]. Clinical trials are being run at present to confirm its therapeutic role in numerous forms of cancer. Because of its innate ability to stimulate interferon-gamma production and potentiate interferon-gamma receptors, it is also under investigation for its immune-modulating properties [2]. Finally, 3,3'-diindolylmethane and several of its analogues appear to modulate drug-metabolising enzymes such as cytochrome P450 via multiple yet distinct pathways [3, 4].

References

25 June 2008, Motexafin gadolinium

Nuclear magnetic resonance imaging (MRI) is a non-invasive, non-radiative medical imaging method of growing clinical importance. Unfortunately, the difference in MRI signal between diseased and healthy tissues is often small. To enhance the visualization of the area of interest, paramagnetic contrast agents are often used, such as gadolinium compounds. "Texaphyrins" (for "Texas-size porphyrins") is the trivial name of a class of synthetic expanded porphyrins first prepared in 1988 by Jonathan Sessler and co-authors at the University of Texas at Austin [1]. The texaphyrins form stable coordination complexes with large metal cations such as lanthanoids. One such complex, the texaphyrin gadolinium(3+) complex known as motexafin gadolinium (CHEBI:50161; MGd), has been extensively studied as a potential MRI-detectable enhancer of X-ray cancer therapy. In addition, it has been found that in cancer cells MGd generates reactive oxygen species such as superoxide and induces apoptosis. In vitro studies show that MGd enhances tumour cell cytotoxicity with both ionizing radiation and a number of chemotherapeutic agents [2]. The California-based company Pharmacyclics, Inc. has been developing MGd (brand name Xcytrin^®) for use in combination with radiation therapy for treatment of brain metastases from lung cancer. According to the company, "MGd has been evaluated in clinical trials involving over 1000 patients and has been found to be generally well-tolerated, without the usual side-effects seen with standard chemotherapy" [3]. Earlier this month, Pharmacyclics announced final data from a Phase 1/2 study showing a high complete response rate in patients with multiple recurrent non-Hodgkin's lymphoma who were treated with MGd in combination with an approved antibody-targeted radiation therapy.

References

28 May 2008, (–)-α-Thujone

Originally formulated in Switzerland, absinthe became most popular in 19th century France. Many creative artists had their lives touched by absinthe, among them Toulouse-Lautrec, Oscar Wilde, Picasso and Vincent van Gogh. Absinthe was classically manufactured from dried wormwood (Artemisia absinthium), anise and fennel, which were steeped overnight in 85% (by volume) ethanol [1]. Popular lore has it that absinthe causes hallucinations, epileptic-like attacks, and bouts of madness for those who drink it [2]. Convulsions resembling epilepsy were observed in humans and induced in animals with toxic doses of absinthe. The essential oils were first implicated, then specifically wormwood, and finally one compound, the monoterpene (–)-α-thujone (CHEBI:9577). Despite (or maybe precisely because of) its popularity, absinthe was cast as a dangerous and addictive psychoactive drug. Between 1905 and 1913 Belgium, Switzerland, the United States, and Italy banned absinthe [1]. The bans were surprising, given that they were not supported by any scientific evidence that absinthe contained enough thujone or other compounds that could lead to "absinthism". An international research effort now offers firm scientific evidence that thujone is not the culprit behind those effects [3]. The authors conclude that the thujone concentration of preban (prior to 1915) absinthe was generally overestimated in the past. Analysis of postban (1915–1988) and modern commercial absinthes (2003–2006) shows that the encompassed thujone ranges of all absinthes are similar, disproving the supposition that a fundamental difference exists between preban and modern absinthes manufactured according to historical recipes. As the authors note, 'all things considered, nothing besides ethanol was found in the absinthes that was able to explain the syndrome "absinthism"'.

References

30 April 2008, 2-deoxy-2-(¹⁸F)fluoro-α-D-glucose

Positron emission tomography (PET) is one of the most sensitive molecular imaging techniques today. PET imaging agents are labelled with radionuclides which decay by the emission of a positron (β⁺), the antimatter counterpart of an electron. After being emitted from the nucleus, the positron travels a short distance in the surrounding matter before it annihilates with an electron. The annihilation produces two γ-rays, which are emitted simultaneously in opposite directions and are then detected by an array of surrounding detectors. Most of the PET imaging probes applied in neurological research have been labelled with either ¹¹C or ¹⁸F.

¹⁸F → ¹⁸O + β⁺ + ν_e
¹⁸F-labelled PET radiopharmaceuticals have the most favourable physical properties because the ¹⁸F nuclide has the best imaging physical characteristics due to a low positron energy. Its half-life of 110 min allows for more complex radiosynthesis, longer in vivo investigation, and commercial distribution to clinical PET centres that lack radiochemistry facilities [1]. Most important examples of ¹⁸F PET imaging probes are 6-(¹⁸F)fluoro-L-dopa, a PET ligand for probing cerebral dopamine metabolism and neuroendocrine tumors, and the glucose analogue 2-deoxy-2-(¹⁸F)fluoro-α-D-glucose (¹⁸FDG; CHEBI:31617). ¹⁸FDG is the best clinically known and successful PET tracer and one of the earliest examples of a PET molecular imaging probe feasible to visualise glucose utilisation in vivo by a metabolic trapping mechanism [2]. All experts in the field agree that there would be no clinical PET imaging today without ¹⁸FDG.

References

26 March 2008, (2-trans,6-trans)-farnesol

Nutria, or coypu (Myocastor coypus), are very large (5–9 kg) rat-like animals, originally introduced into North America, Europe, Asia and Africa from South America for their fur, but which are currently ravaging wetlands across Louisiana and the coast of the Gulf of Mexico. Because of their ability to reproduce at rapid speed (a female may have 3 litters per year of up to 13 young per litter), they are unwieldy to control if released into the wild. Now, Professor Athula Attygalle and his team at the Stevens Institute of Technology, New Jersey, in collaboration with groups at Cornell University and the University of Iowa, have identified several volatile compounds, including terpenoids, fatty alcohols, fatty acids and some of their esters, in the anal scent glands of the species. Using gas chromatographic retention times as well as electron-ionization (EI) and chemical-ionization (CI) mass spectrometry, they have identified the major terpenoid constituents as (2-trans,6-trans)-farnesol [CHEBI:16619; otherwise known as (E,E)-farnesol] and its esters. (2-trans,6-trans)-Farnesol is a sesquiterpene alcohol which is also present in many essential oils such as citronella, neroli, cyclamen, lemon grass, tuberose, rose, musk, balsam and tolu. It is also used in perfumery to emphasize the odours of sweet floral perfumes. By incorporating this compound and its esters into lures as bait, Professor Attygalle's discovery offers an environmentally friendly solution to the problem of removing nutria from sensitive coastal zones and marshlands without detrimentally affecting other species.

Reference

27 February 2008, Pseudocoenzyme B₁₂

Sixty years ago, a crystalline compound, which provided a cure for a previously fatal disease pernicious anaemia, was isolated from liver. This compound has become known as vitamin B₁₂ [1]. In the same year, Dorothy Crowfoot Hodgkin began her attempts to determine the structure of vitamin B₁₂, and in 1964 was awarded the Nobel Prize in Chemistry "for her determinations by X-ray techniques of the structures of important biochemical substances", including penicillin and vitamin B₁₂. Vitamin B₁₂ is biosynthesised in certain bacteria, with animals obtaining their B₁₂ from food or directly from resident B₁₂-synthesising bacteria. All B₁₂ cofactors are cobalt–corrinoid complexes. One of the cobalt axial ligands (designated α) is attached to the corrin nucleus via the nucleotide loop, while the other axial ligand (designated β) can vary. The coenzymatically active forms of the B₁₂ vitamins possess an organic β-axial ligand, either methyl or 5'-deoxy-5'-adenosyl, attached via a physiologically rare carbon-to-cobalt bond. The "classic" B₁₂ cofactors that contain 5,6-dimethylbenzimidazole (DMB) as α-axial ligands are called cobalamins. Pseudocoenzyme B₁₂ (CHEBI:48572) is the most common example of a natural B₁₂ cofactor with an α-axial ligand other than DMB – in this case, adenine [2]. The bacterium Salmonella enterica produces the corrin ring only under anaerobic conditions, but it can form B₁₂ coenzymes aerobically by importing a corrinoid precursor, such as cobinamide (Cbi), and adding appropriate axial ligands. Wild-type S. enterica can use ethanolamine as an aerobic source of carbon and energy in the presence of vitamin B₁₂. It also can synthesise vitamin B₁₂ only when both Cbi and DMB are provided. Anderson et al. [3] have recently demonstrated that mutants of S. enterica isolated for their ability to degrade ethanolamine without added DMB can convert Cbi into pseudo-B₁₂ cofactors. The mutations cause an increase in the level of free adenine and install adenine as cobalt α-ligand instead of DMB. Addition of DMB to these mutants stops the synthesis of pseudo-B₁₂ cofactors and B₁₂ cofactors are produced instead. Wild-type cells make pseudo-B₁₂ cofactors during aerobic growth on propanediol and Cbi, and can use pseudo-B₁₂ for all of their corrinoid-dependent enzymes.

References

30 January 2008, Triclocarban

The urea derivative triclocarban (TCC; CHEBI:48347) is an antibacterial and antifungal compound which for 45 years has been added in the USA and Europe to household and personal care products including bars of soap, body washes, cleansing lotions, wipes and detergents. An estimated 45,000 kg of the product are imported annually for the US market alone. The mechanism of its action involves inhibition of the enzyme enoyl-[acyl-carrier-protein] reductase (NADH) (EC 1.3.1.9), a key enzyme of the type II fatty acid synthase (FAS-II) system. Recently, a new UC Davis study, led by emeritus professor Bill Lasley, an expert on reproductive toxicology, has raised concerns by demonstrating that triclocarban can alter hormonal activity in rats and human cells in the laboratory. The study identified two key effects: in human cells triclocarban increased gene expression that is normally regulated by testosterone; and when male rats were fed triclocarban, testosterone-dependent organs such as the prostate gland grew abnormally large. Also, the mechanism by which triclocarban acts, i.e. by increasing hormone effects, is novel, as all previous studies of endocrine disruptors have found that these generally act by blocking or decreasing hormone effects. Lasley believes that the findings may lead eventually to an explanation for rises in some previously described reproductive problems that to date have been difficult to understand.

Reference

19 December 2007, Salinosporamide A

Salinosporamide A (CHEBI:48045), a chlorinated natural product from the marine bacterium Salinispora tropica, is a 20S proteasome inhibitor currently in phase 1 human clinical trials for the treatment of the bone marrow cancer multiple myeloma as well as solid tumours. It is around 500 times more active than its dechloro analogue salinosporamide B. In a recent publication by researchers in La Jolla, California [1], it was reported that salL, an 849-base-pair gene in the sal biosynthetic cluster, is required for in vivo chlorination of salinosporamide A. Their work has determined that SalL protein catalyses the displacement of L-methionine from the primary metabolite S-adenosyl-L-methionine (SAM; December 2005 ChEBI Entity of the Month) to generate the intermediate 5'-chloro-5'-deoxyadenosine by a nucleophilic substitution reaction. The mechanism has similarities to a known fluorinase FlA from the soil bacterium Streptomyces cattleya [2], which proceeds via a 5'-fluoro-5'-deoxyadenosine intermediate, and is in contrast to the oxidative mechanism that predominates in biological chorinations. Through its use of such an orthogonal biological chlorination mechanism, it is likely that SalL will prove valuable for the biosynthesis of halogenated small molecules.

References

28 November 2007, A,D-di-p-benzi[28]hexaphyrin(1.1.1.1.1.1)

The German astronomer and mathematician August Ferdinand Möbius (1790–1868) is best known for his discovery (in 1858) of a non-orientable two-dimensional surface with only one side, which is now known as the Möbius band. It was independently discovered the same year by another German mathematician, Johann Benedict Listing. 100 years after its discovery, the Möbius topology caught the imagination of chemists [1]. In the 1930s, Erich Hückel predicted that annulenes which contain 4n+2 mobile electrons should be stable (aromatic), and that those with 4n electrons should be unstable (antiaromatic). However, the Hückel rule is reversed for annulenes with a 180° twist (Möbius annulenes) [2]: chemical Möbius bands with 4n electrons are aromatic and those with 4n+2 electrons are antiaromatic. Recently, Stępień et al. [3] have demonstrated that a molecule can be dynamically switched between Hückel and Möbius topologies by changing the polarity of the solvent. This effect was observed in an expanded porphyrin containing two p-phenylene groups. The compound, A,D-di-p-benzi[28]hexaphyrin(1.1.1.1.1.1) (CHEBI:47035) has 28 (i.e. 4n) mobile electrons and is antiaromatic in non-polar solvents such as hexane, as expected from the Hückel rule. However in polar solvents such as chloroform and N,N-dimethylformamide, the molecule changes conformation from “Hückel” (two-sided) to “Möbius” (one-sided) and antiaromaticity is lost. The difference in conformation is brought about by a 90° twist in one of the p-phenylene groups, which can be either parallel to the other p-phenylene group (Hückel topology) or perpendicular (Möbius topology). The two conformers possess vastly different optical signatures: the hexane solution is green and the chloroform solution is blue. Have a virtual tour over the chemical Möbius band!

References

31 October 2007, capsaicin

Capsaicin (CHEBI:3374) is the active component of chilli peppers, plants belonging to the genus Capsicum. First isolated in 1816 but not synthesised in the laboratory until 1930, it is one of a class of related substances known as capsaicinoids. It is an irritant for mammals and produces a sensation of burning in tissues into which it comes into contact. Capsaicin is believed to be synthesised in the interlocular septa of chilli peppers by addition of a branched-chain to vanillylamine. Biosynthesis depends on the gene Pun1 which encodes a putative acyltransferase [1]. In a recent paper [2], Clifford Woolf and his co-workers at Harvard Medical School and Massachusetts General Hospital report that capsaicin can be used in combination with QX-314, a derivative of the commonly used local anaesthetic lidocaine, to produce an anaesthetic which can completely block pain without causing numbness or paralysis. On its own, QX-314 is unable to pass through cell membranes to block their electrical activity: the role of capsaicin is to open large pores called TRPV1 ion channels, which allow the QX-314 to pass through and selectively block the cells' activity. The treatment is thought to have great potential in improving pain treatment during childbirth, dental procedures and surgery.

References

26 September 2007, (–)-geosmin

The chemical origin of the characteristic odour of soil was first investigated in 1891 by the French chemist and politician Marcellin Berthelot, considered by many to be one of the greatest chemists of all time. However, it was not until 1965 that the responsible agent, (–)-geosmin (CHEBI:46702), was first isolated in pure form and the structure assigned. Later investigations concluded that (–)-geosmin is generated, via germacradienol (CHEBI:46734), from the universal acyclic sesquiterpene precursor farnesyl diphosphate (FPP, CHEBI:17407) by an enzyme (UniProtKB Q9X839, IntEnz EC 4.2.3.22) that is encoded by the SCO6073 gene in the soil organism Streptomyces coelicolor A3(2). A recent study by David Cane and his team at Brown University, Rhode Island, has now shown unambiguously that the SCO6073 germacradienol-geosmin synthase of S. coelicolor is a bifunctional enzyme, in which it is the N-terminal half of the protein which converts FPP principally to geramacradienol, while the C-terminal half (previously thought to be catalytically inactive) then rebinds the germacradienol and catalyses its proton-initiated cyclisation to give the (–)-geosmin.

Reference

29 August 2007, imatinib

Protein-tyrosine kinases represent an important class of drug targets, particularly in oncology and inflammation. In a recent study [1], a "chemical proteomics" methodology that enables the capturing of a defined sub-proteome (in this case, protein kinases) on a mixed kinase inhibitor matrix ("kinobeads"), and subsequent analysis by quantitative protein mass spectrometry, has been described. This methodology was applied to three drugs targeting the oncogenic BCR-ABL kinase, which induces chronic myelogenous leukaemia (CML). Quantitative profiling of the drug candidate bosutinib (SKI-606), which is currently undergoing clinical trials, and the marketed drugs imatinib (CHEBI:38918) and dasatinib in K562 cells confirms known targets including ABL and SRC family kinases. Unexpectedly, the receptor tyrosine kinase DDR1 and the metalloflavoprotein oxidoreductase NQO2 (EC 1.10.99.2) were also identified as potent novel targets of imatinib. The function of the "forgotten" enzyme NQO2 (discovered in 1961; re-discovered 36 years later!) is not known but it has been implicated in the detoxification of xenobiotics. It also has been shown to be inhibited by the anti-malarial drugs chloroquine and quinacrine as well as by the red wine component resveratrol [2]. Interestingly, a high expression of NQO2 is found in myeloid cells, which are also the target of imatinib in CML.

References

25 July 2007, water

It is a wet summer this year in Britain and so it may be an appropriate time to reflect on the unique chemical compound known as water (CHEBI:15377). Water was one of the classic "four elements" of antiquity. It was Antoine Lavoisier who showed in the late 18th century that water is composed of two elements, hydrogen and oxygen. Water covers >70% of the Earth's surface and is the only single chemical substance to give its name to a scientific discipline, that of hydrology. Water is the single most important molecule for life on Earth. Most biochemical reactions take place in aqueous solution; water also is a substrate of many of them (hydrolases, hydratases, photosystem II). Crystalline proteins contain significant amounts of water. Some proteins contain single-file water chains that are suggested to be able to conduct protons along their length ("proton wires"). Such proton wires were observed in X-ray structures of the photosynthetic reaction centre from Rhodobacter sphaeroides, bacteriorhodopsin, cytochrome f, cytochrome c oxidase and phosphatidylglycerophosphatase from Listeria monocytogenes [1 and references therein]. Water can play a structural function in proteins, as is shown by the recent X-ray structural determination of a cysteinless plant Kunitz-type protease inhibitor BbCI where a water-mediated hydrogen bond replaces the highly conserved disulfide bridge thought to be crucial for protein structure stabilisation [2].

References

27 June 2007, lapatinib

Lapatinib (CHEBI:38636) is a quinazolinamine-based small molecule that potently inhibits the intracellular tyrosine kinase domains of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2). In March 2007, lapatinib, in the form of its ditosylate monohydrate [Tykerb; GlaxoSmithKline (GSK)], was approved by the US Food and Drug Administration (FDA) for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress HER2 and who have received prior therapy including an anthracycline, a taxane and trastuzumab (Herceptin), the combination of trastuzumab with taxane-based chemotherapy being currently the standard first-line treatment for HER2-positive metastatic breast cancer. GSK also last year filed an application for the drug to the European Medicines Agency and expect approval for its use within Europe later this year. Financial analysts are predicting peak sales for lapatinib of $1.5 billion [Moy, B., Kirkpatrick, P., Kar, S. and Goss, P. (2007) Lapatinib. Nature Reviews Drug Discovery 6, 431–432].

30 May 2007, chlorophyll a

Photosystem I (PSI), a protein supercomplex that contains a reaction centre and light-harvesting complexes, is involved in oxygenic photosynthesis where it is a star performer in energy-gathering terms. It is the most efficient photochemical machine in nature, with almost every photon absorbed by the PSI complex being used to drive electron transport. In a recent issue of Nature, Nathan Nelson and his team at Tel Aviv University report the X-ray crystal structure of plant PSI from pea (Pisum sativum) and reveal that, along with a small number of phylloquinones, Fe₄S₄ clusters and carotenoids, this huge complex binds 168 chlorophyll molecules, with most of these being our Entity of the Month chlorophyll a (CHEBI:18230). Thus, even though chlorophyll is usually thought of as a "cofactor", the sheer bulk of chlorophylls in PSI makes us (ChEBIsts) look at it differently. One can say that PSI is mostly chlorophyll with some proteins wrapped around! [Amunts, A., Drory, O., Nelson, N. (2007) The structure of a plant photosystem I supercomplex at 3.4 Å resolution. Nature 447, 58–63].

25 April 2007, brussalexin A

Phytoalexins are antimicrobial compounds synthesised by plants when stressed which help the weakened plant to defend itself against infection. Soledade Pedras and her research team at the University of Saskatchewan have been using UV irradiation to stress Brussels sprouts (Brassica oleracea var. gemmifera) in order to discover new molecules and have now isolated from their experiments a remarkable new phytoalexin which they name brussalexin A (CHEBI:38130). The compound contains an allyl thiocarbamate group, a structure not previously seen in phytoalexins and whose formation cannot be explained using currently known pathways. Brussalexin A proves to be toxic towards several species of fungus, in particular Sclerotina sclerotiorum, which causes stem rot in many plant families. Pedras' group will now investigate how fungal pathogens break down brussalexin A, with their principal aim being to treat crops with compounds that inhibit these detoxification routes, thus allowing the plants' natural defence mechanisms to work for longer [Pedras, M.S.C., Zheng, Q.-A. and Sarwar, M.G. (2007) Efficient synthesis of brussalexin A, a remarkable phytoalexin from Brussels sprouts. Org. Biomol. Chem. 5, 1167–1169; see also the article "Stressed sprouts hit back" in Chemical Biology 2007, vol. 5.].

28 March 2007, cimicifoetiside A

Cimicifuga foetida is a herbaceous perennial plant native to China where it is used as an antipyretic and analgesic agent in traditional Chinese medicines. Alcoholic extracts from its rhizomes are now being imported into Western markets in order to meet an ever-increasing demand for its North American relative C. racemosa (known commonly as black cohosh, black bugbane or black snakeroot) which is widely used in the United States and Europe as a herbal dietary supplement for the relief of symptoms related to menopause. A collaboration between workers in Kunming, China, and Washington University in the US investigating the constituents of C. foetida has recently resulted in the isolation of a novel cycloartane-type triterpene glycoside which they have named cimicifoetiside A (CHEBI:37779), together with its 25-O-acetyl derivative, named cimicifoetiside B (CHEBI:37780). The compounds are interesting both structurally, in that they possess a relatively uncommon 2-O-acetyl α-L-arabinosyl unit, and physiologically, as they exhibit potent cytotoxicity against human breast cancer cells, suggesting the potential for further examination of these and other cycloartane triterpene glycosides from Cimicifuga spp. for the prevention or treatment of human breast cancers [Sun et al. (2007) Beilstein Journal of Organic Chemistry 3,3].

28 February 2007, beauvericin

Beauvericin (CHEBI:3000) is a cyclodepsipeptide of alternating L-N-methylphenylalanyl and D-α-hydroxyvaleryl residues. Well known as a mycotoxin affecting wheat and other cereal crops, it is produced by several Fusarium species and has also been isolated from the entomopathogenic fungus Beauvaria bassiana . Beauvericin is capable of complexing both alkaline-earth metals and alkali-metal ions and transporting them through membranes in biological systems. New reports of its properties and usage constantly emerge, as exemplified by a very recent publication from two groups in Arizona in which inhibition by beauvericin of metastatic prostate cancer and breast cancer cells, as well as antiangiogenic activity, is demonstrated [Zhan et al. (2007) J. Nat. Prod. 70,227–232 ].

31 January 2007, (–)-epigallocatechin 3-gallate

Catechins (CHEBI:23053) are a group of polyphenolic plant metabolites found extensively in extracts of green, unfermented, tea (Camellia sinensis ). The various health benefits attributed to green tea have until recently been thought to be linked to the antioxidant properties of its constituent catechins. However the use of green tea extract in oral hygiene for several centuries suggests that green tea may also have antibacterial activity. Roman Jerala and his colleagues at the National Institute of Chemistry in Ljubljana, Slovenia, have now, using heteronuclear 2D NMR and fluorescence spectroscopy, studied the properties of (–)-epigallocatechin 3-gallate (EGCG) (CHEBI:4806), the major catechin found in green tea. Their results show that ECGC inhibits the bacterial enzyme DNA gyrase by binding to the ATP binding site of one of its two subunits, known as gyrase B. This subunit catalyses ATP hydrolysis, providing the driving force for supercoiling of DNA, and has been previously investigated as a target for antibacterial drugs. Jerala believes that his findings with EGCG should allow pharmaceutical companies to design novel analogues which improve on EGCG's antibacterial activity without prohibitive side effects emerging [Gradišar, H., Pristovšek, P., Plaper, A. and Jerala, R. (2007) Green tea catechins inhibit bacterial DNA gyrase by interaction with its ATP binding site. J. Med. Chem. 50, 264–271 ; see also: Bradley, D. Tea for who? SpectroscopyNOW.com, January 15, 2007 ].

20 December 2006, tangeretin

The tradition of putting a tangerine (Citrus nobilis var. Tangeriana) into the toe of a Christmas stocking is thought by some to represent the landing within stockings hung up to dry of dowry money which St Nicholas ('Santa Claus') tossed down a chimney in order to rescue several poor maidens from being sold into slavery. In more recent years, however, a more scientific importance of tangerines has emerged, namely that a valuable constituent of their peel (and that of some other citrus fruits) is tangeretin (CHEBI:9400), a polymethoxylated flavone which exhibits a wide range of pharmacological activity. In vitro studies have demonstrated antimutagenic, antiinvasive and antiproliferative effects, while animal research has suggested its potential as both a cholesterol-lowering agent and a protector against Parkinson's disease. More significantly perhaps is the potential of tangeretin as an anti-cancer agent, demonstrated by its inhibition of leukaemic HL-60 cell growth through induction of apoptosis [Hirano et al. (1995) Br. J. Cancer 72, 1380-1388 ], although it must be noted that in the presence of dietary tangeretin a neutralization of the tumour-inhibitory effect of the anti-cancer drug tamoxifen (CHEBI:9396) is observed [Bracke et al. (1999) J. Natl. Cancer Inst. 91, 354-359 ]. A very recent report [Takano et al. (2007) Am. J. Physiol. Cell Physiol. 292, C353–C361 ] highlights the ability of tangeretin and similar polymethoxyflavones to protect cells against endoplasmic reticulum (ER) stress.

1 November 2006, (R)-amygdalin

(R)-Amygdalin (CHEBI:17019; commonly known merely as 'amygdalin' or as 'Vitamin B17') is a by-product of the fruit industry. A naturally occurring cyanogenic glycoside, it is found in many food plants such as the kernels of apricots, almonds and apples and is used as a main constituent in commercial preparations of laetrile, a purported therapeutic agent. George John and Praveen Kumar Vemula from the City College of the City University of New York have now used an enzyme catalysis route to make amygdalin-based amphiphiles (molecules with parts which engage separately in hydrophilic and hydrophobic interactions) which showed unprecedented gelation properties in a wide range of solvents. Using further enzyme catalysis, the supramolecularly organised hydrogels thus formed were then employed as a successful drug-delivery vehicle for curcumin, a well known drug with anti-inflammatory and anti-cancer properties. The project is part of John's ongoing work on the design and development of new soft nanomaterials derived from plant/crop-based renewable feedstocks [John, G. and Vemula, P.K. (2006) Design and development of soft nanomaterials from biobased amphiphiles. Soft Matter 2, 909-914].

27 September 2006, ciguatoxin

The huge ladder-like polycyclic ether ciguatoxin (CHEBI:36467) is a marine toxin found in tropical fish. It is produced by an epiphytic dinoflagellate, Gambierdiscus toxicus, and transferred to herbiverous and carnivorous fish through the aquatic food chain. Ciguatoxin and its congeners are the principal causative agents of ciguatera poisoning, the symptoms of which include gastrointestinal, cardiovascular and neurological disorders which can last for many years. Ciguatoxin is one of the most lethal natural products known with a toxicity almost 300 times that of tetrodotoxin, the infamous compound found in pufferfish. Until now, detailed biological studies, as well as the development of therapeutic methods for ciguatera, have been hampered by the very limited supply of the natural product (the yield from 4000 kg of moray eels is only 0.35 mg). Professor Masayuki Inoue and his colleagues in the Hirama Resarch Group at Tohoku University, Sendai, have now published the first total synthesis of ciguatoxin and one of its hydroxylated derivatives, an achievement that will undoubtedly lead to the development of strategies to contol ciguatera food poisoning [M. Inoue et al. (2006) Total Synthesis of Ciguatoxin and 51-HydroxyCTX3C. J. Am. Chem. Soc. 1280, 9352-9354].

30 August 2006, 19-norandrosterone

19-Norandrosterone (CHEBI:36412) is a naturally produced steroid and a metabolite of the anabolic steroid nandrolone, which is still used illegally by some athletes to boost muscle mass. Evidence for nandrolone abuse is normally provided from analysis of urine samples for 19-norandrosterone, although current tests are unable to distinguish whether the norandrosterone is of synthetic or physiological origin (it is produced naturally in the adrenal glands, gonads and placenta). Researchers at the German Sport University Cologne and the Montreal Anti-doping Laboratory at the INRS-Institut Armand-Frappier have recently developed a technique called gas chromatography combustion isotope ratio mass spectrometry, which can distinguish between the two by analysing the ratio of ¹³C to ¹²C in the urine samples. The method can detect concentrations of 19-norandrosterone as low as 2 ng per ml of urine (the level currently allowed by the World Anti-Doping Agency) and may help to resolve cases where athletes have elevated levels of 19-norandrosterone in their urine but insist that they have never taken steroids [Hebestreit et al. (2006) Analyst 131, 1021-1026].

24 July 2006, ozone

Ozone (O₃; CHEBI:25812), one of the most toxic inorganic compounds known, is present in low concentrations throughout the Earth's atmosphere. Ground-level ozone, formed by reaction of hydrocarbons and nitrogen oxides with sunlight, is an air pollutant with harmful effects on lung function. A current prolonged period of hot sunny weather across the UK, with daytime temperatures over 30 degrees Celsius, combined with a flow of air from continental Europe containing ozone precursor particulates, led during July of this year to the UK government department Defra issuing a Smog Warning. Levels of ozone across the UK are monitored by the Air Quality Archive, which also offers health advice to those who may be particularly sensitive to air pollution.

27 June 2006, C₆₀ fullerene

C₆₀ fullerene (CHEBI:33128; known also as buckminsterfullerene, footballene and soccerballene) was discovered in 1985 by Sir Harold Kroto in the UK and Richard E. Smalley and Robert F. Curl, Jr. in the USA. These three researchers shared The 1996 Nobel Prize in Chemistry for their discovery. C₆₀ fullerene's atoms are bonded together into a highly symmetrical, hollow polygon structure with the same geometry as that of a football (soccerball). Named after the architect Richard Buckminster "Bucky" Fuller whose geodesic dome design is similar to the molecular structure of C₆₀, these unique structures, also known as buckyballs, have led to an entirely new branch of chemistry. A recent review lists several interesting biological and pharmacological properties of C₆₀ fullerene and derivatives, such as nitric oxide synthase inhibition, nitric oxide-scavenging activity, reactive oxygen species-generating activity, superoxide dismutase mimic properties, and HIV reverse transcriptase and RNA polymerase inhibition [Satoh, M. and Takayanagi, I. (2006) Pharmacological studies on fullerene (C₆₀), a novel carbon allotrope, and its derivatives. J. Pharmacol. Sci. 100, 513–518]. The ChEBI team find it fitting that this 10th anniversary of the Fullerene Nobel Prize should coincide with the staging of the 2006 Football World Cup!

31 May 2006, porphyra-334

The mycosporine-like amino acid porphyra-334 (CHEBI:35671) was first isolated in 1979 from the red alga Porphyra tenera Kjelman. Morris Srebnik and his team at The Hebrew University of Jerusalem have now also isolated porphyra-334 from the aquatic bacterium Aphanizimenon flos-aquae and compared its UVA absorption with that of some commercial sun-care products. Their results show that porphyra-334 provides an equivalent of sun protection factor (SPF) 4 against UVA rays. Furthermore, it dissipates UV energy without creating any reactive species which might cause a phototoxic effect on living organisms, suggesting its possible further development as a commercial sunscreen [Torres, A., Enk, C.D., Hochberg, M. and Srebnik, M. (2006) Porphyra-334, a potential natural source for UVA protective sunscreens. Photochem. Photobiol. Sci. 5, 432–435].

26 April 2006, adenosine 5'-monophosphate 1-oxide

Royal jelly is a sticky, creamy white secretion produced by honey bees to feed the larvae of the colony until they develop to the desired rank. The larvae to develop into the queen will receive only royal jelly as their food source. Royal jelly has been claimed to have various beneficial effects on human health. It is a mixture of vitamins, amino acids, proteins, sugars and lipids, as well as the hero of this month, adenosine 5'-monophosphate 1-oxide (CHEBI:35483), or AMP 1-oxide. AMP 1-oxide was previously shown to inhibit the growth of tumor cells in culture as well as vaccinia virus replication by the blockade of translation of virus mRNAs. However, there have been no reports showing the distribution of adenosine 1-oxide derivatives in natural products, or the activity on the nervous system. Recently, Hattori and co-authors have shown that AMP 1-oxide is an active component of royal jelly that induces neuronal differentiation of pheochromocytoma PC12 cells. AMP 1-oxide induced neurite (process)-formation, inhibited cell growth, and facilitated neurofilament M expression, which suggests that AMP 1-oxide stimulates neuronal differentiation of PC12 cells similarly to nerve growth factor (NGF). [Hattori, N., Nomoto, H., Mishima, S., Inagaki, S., Goto, M., Sako, M. and Furukawa, S. (2006) Identification of AMP N₁-oxide in royal jelly as a component neurotrophic toward cultured rat pheochromocytoma PC12 cells. Biosci. Biotechnol. Biochem. 70, 897–906].

22 March 2006, (25R)-5β-spirostan-1β,3α-diol

(25R)-5β-spirostan-1β,3α-diol (CHEBI:35370) is a previously unknown naturally occurring steroidal sapogenin which has been recently isolated from the bulbs of a southern African grassland lily, Ornithogalum tenuifolium. The steroid monomers stack to form one-dimensional chains that interlock with neighbouring polymers, with the overall structure of the natural product almost perfectly mimicking a man-made zip-fastener. It is the first-known zip-like structure to be composed of individual steroid molecules rather than the more usual coupled polymer chains such as those found in DNA [Munro et al. (2006) New J. Chem. 30, 197–207].

22 February 2006, apratoxin A

Apratoxins are marine cyanobacterial cyclodepsipeptides containing discrete polypeptide and polyketide domains. Apratoxin A (CHEBI:35212) demonstrates potent cytotoxicity against tumor cell lines through an unknown mechanism. In a recent communication, Luesch and co-authors used a functional genomics approach, including mRNA expression analysis and genome-wide arrayed cDNA overexpression, to elucidate the molecular basis for this activity. The authors conclude that apratoxin A mediates tumor cytotoxicity through the induction of cell cycle arrest and of apoptosis, which is at least partially initiated through antagonism of fibroblast growth factor (FGF) signalling [Luesch, H., Chanda, S.K., Raya, R.M., Dejesus, P.D., Orth, A.P., Walker, J.R., Izpisúa Belmonte, J.C. and Schultz, P.G. (2006) A functional genomics approach to the mode of action of apratoxin A. Nature Chemical Biology 2, 158–167].

7 December 2005, S-adenosyl-L-methionine

S-adenosyl-L-methionine (AdoMet; SAM; CHEBI:15414) is an important sulfonium intermediate in one-carbon metabolism, the 'active methyl' of the methionine being donated to an acceptor molecule by transmethylation with production of S-adenosyl-L-homocysteine. A recent communication reports the synthesis of analogues with extended allylic and propargylic chains replacing the methyl group and shows their suitability as cofactors for DNA methyltransferases, providing a new method for sequence-specific covalent derivatization of DNA.

26 October 2005, quinacrine

The human prion protein in its normal form, PrP^c, plays an important role in maintaining several cell functions. The pathogenic form, PrP^Sc, has an essentially identical primary structure but is folded differently and displays different physiological interactions giving rise to prion diseases such as variant CJD. Quinacrine (CHEBI:8711), an acridine derivative formerly widely used as an antimalarial, is known to bind to PrP^c prions and is currently undergoing human clinical trials through the British Medical Research Council to investigate its efficacy in combating such prion diseases.

22 September 2005, tomatine

The glycoalkaloid tomatine (CHEBI:9630) is a steroidal saponin that occurs in the leaves of wild tomato plants where it inhibits the growth of various fungi and bacteria. Researchers at the University of East Anglia in the UK have recently published a one-pot synthetic route to the tetrasaccharide part of tomatine which should facilitate studies into understanding the ecological relationships between plants and fungi [Jones, N.A., Nepogodiev, S.A. and Field, R.A. (2005) Organic & Biomolecular Chemistry 3, 3201–3206).

31 August 2005, rofecoxib

Rofecoxib (CHEBI:8887), a cyclooxygenase (COX) inhibitor, was formerly marketed by Merck and Co. under the trade name VIOXX. Its specificity for only one form of the enzyme, COX-2, allowed it to reduce inflammation and pain while minimizing undesired gastrointestinal adverse effects, common with other nonsteroidal anti-inflammatory drugs. On August 19 2005 a US jury found Merck negligent in the death of a man who used it and awarded his widow $253.4m. Merck is to appeal against the decision. A view of the molecule and some further reading are available here.

27 July 2005, ATTA-Eu³⁺

A dioxygen molecule in an excited singlet state, known as singlet molecular oxygen (¹O₂), reacts with many kinds of biomolecules, such as DNA, proteins and lipids. Researchers at the Chinese Academy of Sciences have recently reported the synthesis and characterization of ATTA-Eu³⁺ (CHEBI:33025), the first europium(3+) chelate-based phosphorescence probe specific for time-resolved luminescence detection of ¹O₂. The structure of ATTA-Eu³⁺ is shown in the abstract of this report [Song, B., Wang, G. and Yuan, J. Chem. Commun., 2005, 3553–3555].

29 June 2005, pelargonidin 3-glucoside

The predominant pigment in strawberries (Fragaria sp.) is pelargonidin 3-glucoside (CHEBI:31967). One of three anthocyanins which contribute to the red colour in ripe fruit, it is present at a concentration of around 900 μmol/kg and metabolised in humans principally via formation of various pelargonidin monoglucuronic acid conjugates. A view of the molecule is shown here.

25 May 2005, ellagic acid

Ellagic acid [CHEBI:4775] is a fused four-ring polyphenol found abundantly in various fruits, nuts and vegetables. It is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and oesophagus of rodents, and TPA-induced tumour promotion in mouse. Studies suggest that the mechanisms of mutagenesis and carcinogenesis involve adduct formation with DNA, thus masking binding sites to be occupied by the mutagen or carcinogen. A representation of the molecule is available here.

27 April 2005, vancomycin

Vancomycin [CHEBI:28001], a glycopeptide isolated from Streptomyces orientalis, inhibits a specific step in the synthesis of the peptidoglycan layer in Staphylococcus aureus and Clostridium difficile. For over 40 years it has been used to kill bacteria when no other drug works and has become known as the "antibiotic of last resort". However, in recent years vancomycin-resistant enterococci (VRE) have emerged, prompting restrictions in the drug's use. A 3-D representation of the molecule is available here.

16 March 2005, cisplatin

Cisplatin [CHEBI:27899], the structure of which is incorporated into the ChEBI logo, is a square planar platinum complex widely used for the treatment of a variety of tumours. Its mode of action involves loss of its Cl⁻ ligands and binding mainly to the N-7 atoms of a pair of guanine bases on either the same or adjacent strands of DNA, thus causing distortion of the DNA structure and inhibition of cell repair. A diagram showing such linking occurring between adjacent DNA strands is available here.