Analogues of Thiolactomycin as Potential Antimalarial Agents

Jones, Sadie; Urch, Jonathan E.; Kaiser, Marcel; Brun, Reto; Harwood, John L.; Berry, Colin; Gilbert, Ian H.

doi:10.1021/jm049067d

Cited by 102 publications

(73 citation statements)

References 34 publications

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“…A greater understanding of this metabolic crossroad in BSFs may facilitate the discovery of drugs to treat African sleeping sickness. Recently, research on the structures of type II enzymes (62) has renewed interest in designing more selective drugs against previously validated FAS targets (63,64). Trypanosomes, however, may turn out to be more susceptible to new classes of natural product-based inhibitors of type II FAS (65,66).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial Fatty Acid Synthesis in Trypanosoma brucei

Stephens¹,

Lee²,

Paul³

et al. 2007

Journal of Biological Chemistry

111

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Whereas other organisms utilize type I or type II synthases to make fatty acids, trypanosomatid parasites such as Trypanosoma brucei are unique in their use of a microsomal elongase pathway (ELO) for de novo fatty acid synthesis (FAS). Because of the unusual lipid metabolism of the trypanosome, it was important to study a second FAS pathway predicted by the genome to be a type II synthase. We localized this pathway to the mitochondrion, and RNA interference (RNAi) or genomic deletion of acyl carrier protein (ACP) and ␤-ketoacyl-ACP synthase indicated that this pathway is likely essential for bloodstream and procyclic life cycle stages of the parasite. In vitro assays show that the largest major fatty acid product of the pathway is C16, whereas the ELO pathway, utilizing ELOs 1, 2, and 3, synthesizes up to C18. To demonstrate mitochondrial FAS in vivo, we radiolabeled fatty acids in cultured procyclic parasites with

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Section: Discussionmentioning

confidence: 99%

Mitochondrial Fatty Acid Synthesis in Trypanosoma brucei

Stephens¹,

Lee²,

Paul³

et al. 2007

Journal of Biological Chemistry

111

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“…29 TLM exhibits moderate in vitro and potent in vivo activity against many pathogens such as Gram-positive and Gram-negative bacteria 30 including Mycobacterium tuberculosis 31 and malaria parasites. 32 TLM inhibits the type II cell wall fatty acid synthesis (FAS II) in bacteria and plants, 33 which explains the antibacterial and antiparasitical properties of TLM. Because TLM is not toxic in mammals, 30 over 100 synthetic, mainly nonpolar TLM congeners have been investigated to establish structure activity relationships (SAR) and molecular mechanisms of action of drug candidates with the common TA ring system.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Detection, Identification, and Occurrence of Thiotetronic Acids in Drinking Water from Underground Sources by Electrospray Ionization-High Field Asymmetric Waveform Ion Mobility Spectrometry-Quadrupole Time-of-Flight-Mass Spectrometry

2015

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Vous avez des questions? Nous pouvons vous aider. Pour communiquer directement avec un auteur, consultez la première page de la revue dans laquelle son article a été publié afin de trouver ses coordonnées. Si vous n'arrivez pas à les repérer, communiquez avec nous à PublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. Questions? Contact the NRC Publications Archive team atPublicationsArchive-ArchivesPublications@nrc-cnrc.gc.ca. If you wish to email the authors directly, please see the first page of the publication for their contact information. NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. For the publisher's version, please access the DOI link below./ Pour consulter la version de l'éditeur, utilisez le lien DOI ci-dessous.http://doi.org/10.1021/acs.analchem.5b02372Access and use of this website and the material on it are subject to the Terms and Conditions set forth at Detection, identification, and occurrence of thiotetronic acids in drinking water from underground sources by electrospray ionizationhigh field asymmetric waveform ion mobility spectrometry-quadrupole time-of-flight-mass spectrometry Lyczko, Jadwiga; Beach, Daniel; Gabryelski, Wojciech http://nparc.cisti-icist.nrc-cnrc.gc.ca/fra/droits L'accès à ce site Web et l'utilisation de son contenu sont assujettis aux conditions présentées dans le site LISEZ CES CONDITIONS ATTENTIVEMENT AVANT D'UTILISER CE SITE WEB. NRC Publications Record / Notice d'Archives des publications de CNRC:http://nparc.cisti-icist.nrc-cnrc.gc.ca/eng/view/object/?id=3e630c3f-58ee-4b4d-9b24-41b2b10f83cf http://nparc.cisti-icist.nrc-cnrc.gc.ca/fra/voir/objet/?id=3e630c3f-58ee-4b4d-9b24-41b2b10f83cf ABSTRACT: This paper demonstrates that electrospray ionization (ESI) with differential ion mobility spectroscopy (FAIMS) and "soft" mass spectrometry (MS) provide unique analytical capabilities that led to the discovery of sulfurcontaining polar congeners of thiotetronic acid (TA) in drinking water from underground sources in Canada and the United States. Polar TAs accumulate in underground aquifers and appear to be the most abundant class of organic compounds in bottled water but cannot be detected by conventional mass spectrometry methods. We show that normally stable TAs are converted into very reactive ions in ESI which have to be analyzed using special conditions in ESI-FAIMS-MS to avoid extensive dissociation and ion/molecule reactions. De novo identification of 10 TAs was accomplished by the comparative tandem mass spectrometry analysis of authentic TA derivatives from groundwater samples and synthetic TA analogues prepared for this study. We present highlights of gas phase ion chemistry of polar TAs to explain their unique properties and reactivity. TA derivatives were originally isola...

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“…Experimental details for assays of the growth inhibition of Leishmania donovani axenic amastigotes have been reported previously (15). Amastigotes of Leishmania donovani strain MHOM/ET/67/L82 were grown in axenic culture at 37°C in synthetic minimal medium (12), at pH 5.4, supplemented with 10% heat-inactivated fetal bovine serum under an atmosphere of 5% CO 2 in air.…”

Section: Preparation Of Compoundsmentioning

confidence: 99%

Quinuclidine Derivatives as Potential Antiparasitics

Cammerer

Jimenez

Jones

et al. 2007

Antimicrob Agents Chemother

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There is an urgent need for the development of new drugs for the treatment of tropical parasitic diseases such as Chagas' disease and leishmaniasis. One potential drug target in the organisms that cause these diseases is sterol biosynthesis. This paper describes the design and synthesis of quinuclidine derivatives as potential inhibitors of a key enzyme in sterol biosynthesis, squalene synthase (SQS). A number of compounds that were inhibitors of the recombinant Leishmania major SQS at submicromolar concentrations were discovered. Some of these compounds were also selective for the parasite enzyme rather than the homologous human enzyme. The compounds inhibited the growth of and sterol biosynthesis in Leishmania parasites. In addition, we identified other quinuclidine derivatives that inhibit the growth of Trypanosoma brucei (the causative organism of human African trypanosomiasis) and Plasmodium falciparum (a causative agent of malaria), but through an unknown mode(s) of action.Leishmaniasis and Chagas' disease are parasitic diseases caused by the protozoan parasites Leishmania spp. and Trypanosoma cruzi, respectively. Together, both diseases are responsible for high rates of mortality and morbidity, especially in tropical regions of the world. With increasing problems due to resistance and clinical efficacy, the drugs currently used to treat these diseases are becoming increasingly less effective, resulting in the urgent need for new drug candidates in this area.A particular area of interest are the enzymes of the sterol biosynthesis pathway; these provide attractive targets because the parasites that cause these diseases have ergosterol and other 24-alkylated sterols as the principal sterols present in the plasma membrane, while humans have cholesterol. Encouragingly, a number of enzymes in the sterol biosynthetic pathway have been studied as potential drug targets in these organisms and have shown great promise. Thus, 14␣-demethylase (9, 17-20, 29, 30, 38, 41, 42, 45), sterol 24-methyltransferase (9, 20-24, 32, 44, 46, 48), 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase (8, 40), squalene epoxidase (18, 39), squalene synthase (SQS) (7,31,33,36,37), and farnesyl pyrophosphate synthase (25-27, 50) have been studied both individually and in combination, with various degrees of success.The enzyme SQS, which catalyzes the condensation of two molecules of farnesyl pyrophosphate to produce squalene, has been identified as a potential drug target for the inhibition of cholesterol biosynthesis in humans (5). The activities of a variety of compounds, including bisphosphonates, benzylamines, squalestatins, and quinuclidines, against mammalian enzymes have been investigated. One class of compounds whose activities against mammalian SQS have been studied extensively are the arylquinuclidines. These compounds are protonated at physiological pH and are thought to mimic a high-energy carbocation intermediate in the reaction pathway. We are interested in this class of molecules and recently demonstrated that 3-biphenyl-4-y...

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Analogues of Thiolactomycin as Potential Antimalarial Agents

Cited by 102 publications

References 34 publications

Mitochondrial Fatty Acid Synthesis in Trypanosoma brucei

Mitochondrial Fatty Acid Synthesis in Trypanosoma brucei

Detection, Identification, and Occurrence of Thiotetronic Acids in Drinking Water from Underground Sources by Electrospray Ionization-High Field Asymmetric Waveform Ion Mobility Spectrometry-Quadrupole Time-of-Flight-Mass Spectrometry

Quinuclidine Derivatives as Potential Antiparasitics

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