Uridine 5'-diphosphate glucose analogs. Inhibitors of protein glycosylation that show antiviral activity

. Chem. 28:40-46, 1985), has a potent and selective activity against the intracellular and extracellular stages of Trypanosoma cruzi in vitro. It had a 50% inhibitory concentration of less than 5 ,Ig/ml for T. cruzi extracellular cultured forms (epimastigote) and of 25 ,ug/ml for T. cruzi intracellular forms (amastigote) growing inside J774G8 macrophagelike cells. In contrast, the 50% inhibitory concentration was 100 ,ug/ml or greater for cultured mammalian cells and 180 ,ug/ml for the proliferation of mouse spleen lymphocytes. Furthermore, the addition of P536 (50 ,ug/mI) The flagellated protozoan Trypanosoma cruzi is the causal agent of American trypanosomiasis or Chagas' disease (1, 12). T. cruzi exists as epimastigotes (preinfective forms) and metacyclic trypomastigotes (infective forms). The latter are transmitted to mammals by Triatominae insects, where they differentiate into a nonreplicative bloodstream form (trypomastigote) that can infect some types of host cells dividing intracellularly as amastigotes (12).Few drugs are available for the treatment of T. cruzi infections, although heterocyclic drugs such as nifurtimox and benznidazole can ameliorate Chagas' disease (8). However, they have little or no effect on the chronic phase of the disease (14). The intracellular stage is perhaps the most important, since the protozoan is protected not only from the immune system but also from the action of some drugs (8,12). Alternatively, the host cell membrane may be a barrier impermeable to the drug, or the host cell may inactivate it. Therefore, drugs that affect the intracellular forms of the parasite are of particular interest (5,14). In the present study we describe the antitrypanosomic activity of P536, a compound synthesized as an analog of UDP-glucose and previously described as an antiviral agent (9). MATERIALS AND METHODSMaterials. The synthesis of the UDP-glucose analog P536 (Fig. 1) has been described previously (9). P536 was solubilized in water at 10 mM.Media and cells. Human epithelial carcinoma HeLa cells and African green monkey Vero cells were grown in Dulbecco modified Eagle (DME) medium (GIBCO Laboratories) supplemented with calf serum. Murine macrophage J774 68 cells were grown in DME medium plus 10% fetal calf serum (FCS) (GIBCO). Mouse spleen lymphocytes were obtained after removing the erythrocytes by hypotonic lysis and suspended in DME medium plus 5% FCS as described previously (2). T. cruzi, Tulahuen strain, kindly supplied by John David, was cultured continuously in cultured liver infusion-tryptose (LIT) medium supplemented with 10% * Corresponding author.FCS at 27°C, and harvested in the stationary phase as described previously (10). Under those conditions, the medium contained a mixture of the different stages (65 to 75% epimastigotes, 10 to 15% trypomastigotes, and 5 to 10% intermediate forms). A purified population of epimastigotes was obtained from experimental growing cultures which contained more than 99% epimastigotes (2).Infection of the J774 macrophage cell line with T. cr...

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“…The synthesis of the UDP-glucose analog P536 (Fig. 1) has been described previously (9). P536 was solubilized in water at 10 mM.…”

Section: Methodsmentioning

confidence: 99%

Activity of P536, a UDP-glucose analog, against Trypanosoma cruzi

Alcina

Fresno

Alarcón

1988

Antimicrob Agents Chemother

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“…Compounds that interfere with protein glycosylation show a variety of biological effects, such as inhibition of the replication of enveloped animal viruses [248].…”

Section: Kitsonmentioning

confidence: 99%

Squaryl Molecular Metaphors – Application to Rational Drug Design and Imaging Agents

Kitson¹

2017

J Diagn Imaging Ther

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Molecular Metaphors is the application of squaryl building blocks towards creative functional group chemistry to produce lead compounds and imaging agents. This strategy is applied to rational drug design and to various imaging agents that would normally contain conventional functional group chemistry. These, include carboxylic acids, α-amino acids, peptide bonds and phosphonates. Moreover, the squaryl metaphor is a precursor to complex organic molecules involving functional group interchange (FGI) and rearrangements. This article discusses the application of these metaphors in the area of neurochemistry, especially NMDA receptors. An important area of drug design is the inhibition of angiotensin II enzyme by the use of losartan. This commercial drug contains a tetrazole moiety that can be modified using the squaryl group to give a semisquarate derivative. These concepts can extend to the semisquarate of ibuprofen. Moreover, a discussion on peptidomimetics regarding the substitution of the peptide bond for squaramide allows for a change in the biological properties due to modification at the peptide bond. Furthermore, the topic on how squaryl metaphors can be exploited primarily by the central 1,3-hydroxyamide sequence to the generation of a novel class of HIV protease inhibitors. Also, squaryl metaphors can be used to develop potential inhibitors of glutathione and novel anti-migraine drugs. The discussion continues on the design of anticancer drugs: in particular, a novel class of metalloproteases, including phosphonates for semisquaramides, leading to squaryl nucleosides. This review concludes with the application of squaryl metaphors in the design of positron emission tomography (PET) and magnetic resonance imaging (MRI) agents towards theranostics. describe the ability of individual functional chemical groups to mimic other moieties [2,3]. KeywordsErlenmeyer rationalised these concepts and categorised isosteres into atoms, ions and molecules based on the valence level of electrons [4]. A further understanding by Friedman led to the term bioisosterism to include all atoms and molecules that fit the broadest definition of isosteres [5]. This approach was independent of whether the drug was an agonist or an antagonist towards biological activity.Moreover, Thornber applied the term bioisosterism to include subunits, groups or molecules that possess physicochemical properties of similar biological effects [6]. Finally, in 1991 Burger widened the definition of bioisosteres to include compounds or groups that possess similar molecular shapes and volumes independent of agonists or antagonists [7]. REVIEW ARTICLE Squaryl KitsonThese bioisosteres would require approximately the same distribution of electrons and give a high probability of generating comparable physical properties such as hydrophobicity [8]. Currently, bioisosterism is one of the most useful tools to the medicinal chemist in rational drug design and in particular regarding the carboxylic acid bioisosteres [9]. The carboxylic acid functional ...

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“…With the availability of 5 0 -uridyl-carbamate 14 11,24 and the propensity of carbamates to react with isocyanates 25 , an alternative pathway opens for allophanates of types 9-11. Since a-D-glycosyl-isocyanates 23 can be synthesized in a stereoselective manner, the reactions of urea 13 and carbamate 14 can expectedly be extended to those isocyanate derivatives as well to obtain mimics 100 of UDP sugars.…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%