S-Adenosylhomocysteine hydrolase of the protozoan parasite Trichomonas vaginalis: Potent inhibitory activity of 9-(2-deoxy-2-fluoro-β,d-arabinofuranosyl)adenine

Shokar, Ajit; Au, Aaron; An, Seung Hwan; Tong, Elsie; Garza, Gabriel; Zayas, Jessica; Wnuk, Stanislaw F.; Land, Kirkwood M.

doi:10.1016/j.bmcl.2012.03.087

Cited by 11 publications

(5 citation statements)

References 23 publications

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“…TvagENT3 is functionally related to the broad specificity T. brucei P1‐type transporters (De Koning & Jarvis, 1999), although the relatively high affinity for cytidine may be unique amongst protozoan transporters characterized to date, and like P1, its broad specificity/high affinity should be valuable in targeting cytotoxic nucleoside analogues to the T. vaginalis interior (Geiser et al., 2005; Hulpia et al., 2019; Ranjbarian et al., 2017). Indeed, we have very recently reported the identification of a series of strongly antitrichomonal nucleoside analogues (Natto et al., 2021) and other nucleoside analogues with activity against this parasite have been reported (Munagala & Wang, 2003; Shokar et al., 2012).…”

Section: Discussionmentioning

confidence: 98%

“…This makes the parasites vulnerable to inhibitors of key enzymes of the nucleoside salvage pathways and to subversive substrates. Nucleoside analogues with strong antitrichomonal activity have been identified and include formycin A (Munagala & Wang, 2003), adenine arabinoside, 2′‐F,2′‐deoxyadenosine, and 2′‐F,2′‐deoxyarabinoadenosine (Shokar et al., 2012). Very recently, we reported on a range of 7‐substituted,7‐deazaadenosine analogues with mid‐nanomolar activity against T. vaginalis in vitro and one compound, 7‐(4‐Cl‐phenyl),7‐deazaadenosine, was shown to be efficacious in a murine model of vaginal trichomonad infection (Natto et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter

Natto

Miyamoto

Munday

et al. 2021

Molecular Microbiology

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Trichomoniasis is a common and widespread sexually‐transmitted infection, caused by the protozoan parasite Trichomonas vaginalis. T. vaginalis lacks the biosynthetic pathways for purines and pyrimidines, making nucleoside metabolism a drug target. Here we report the first comprehensive investigation into purine and pyrimidine uptake by T. vaginalis. Multiple carriers were identified and characterized with regard to substrate selectivity and affinity. For nucleobases, a high‐affinity adenine transporter, a possible guanine transporter and a low affinity uracil transporter were found. Nucleoside transporters included two high affinity adenosine/guanosine/uridine/cytidine transporters distinguished by different affinities to inosine, a lower affinity adenosine transporter, and a thymidine transporter. Nine Equilibrative Nucleoside Transporter (ENT) genes were identified in the T. vaginalis genome. All were expressed equally in metronidazole‐resistant and ‐sensitive strains. Only TvagENT2 was significantly upregulated in the presence of extracellular purines; expression was not affected by co‐culture with human cervical epithelial cells. All TvagENTs were cloned and separately expressed in Trypanosoma brucei. We identified the main broad specificity nucleoside carrier, with high affinity for uridine and cytidine as well as purine nucleosides including inosine, as TvagENT3. The in‐depth characterization of purine and pyrimidine transporters provides a critical foundation for the development of new anti‐trichomonal nucleoside analogues.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter

Natto

Miyamoto

Munday

et al. 2021

Molecular Microbiology

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“…The lack of efficacy observed with the 5′-norcarbocyclic uridine analogues is consistent with a study that reported little or no inhibition of T . vaginalis growth with modified uridine analogues, but that same study did identify some adenosine analogues, including adenine arabinoside, 2′-F,2′-deoxyadenosine, and 2′-deoxy-2′-fluoroarabinoadenosine, with substantial antitrichomonal efficacy . In addition, it was shown that 2-F,2′-deoxyadenosine is a substrate of T .…”

Section: Discussionmentioning

confidence: 99%

Deazapurine Nucleoside Analogues for the Treatment of Trichomonas vaginalis

et al. 2021

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Trichomoniasis is the most common nonviral sexually transmitted disease in humans, but treatment options are limited. Here, we report a resorufin-based drug sensitivity assay for high-throughput microplate-based screening under hypoxic conditions. A 5203-compound enamine kinase library and several specialized compound series were tested for the inhibition of Trichomonas growth at 10 μM with Z′ values of >0.5. Hits were rescreened in serial dilution to establish an IC50 concentration. A series of 7-substituted 7-deazaadenosine analogues emerged as highly potent anti-T. vaginalis agents, with EC50 values in the low double digit nanomolar range. These analogues exhibited excellent selectivity indices. Follow-up medicinal chemistry efforts identified an optimal ribofuranose and C7 substituent. Several nucleosides rapidly cleared cultures of T. vaginalis at a concentrations of just 2 × EC50. Preliminary in vivo evaluation in a murine trichomoniasis model (Tritrichomonas foetus) revealed promising activity upon topical administration, validating purine nucleoside analogues as a new class of antitrichomonal agents.

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“…Nucleosides bearing fluorine or fluorinated substituents within the carbohydrate moiety have been used successfully in many biochemical research studies and therapeutic treatments. As an example, the ability of 9-(2-deoxy-β-D-arabinofuranosyl)adenine to completely inhibit the protozoan parasite Trichomonas vaginalis (Shokar et al, 2012), as well as its antibacterial (Gao et al, 2015) and antitrypanosomal (Ranjbarian et al, 2017) effect, have been reported. Significant antiviral activity was also confirmed for their dideoxy analogs.…”

Section: Discussionmentioning

confidence: 99%

Hormopriming to Mitigate Abiotic Stress Effects: A Case Study of N9-Substituted Cytokinin Derivatives With a Fluorinated Carbohydrate Moiety

et al. 2020

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Drought and salinity reduce seed germination, seedling emergence, and early seedling establishment, affect plant metabolism, and hence, reduce crop yield. Development of technologies that can increase plant tolerance of these challenging growth conditions is a major current interest among plant scientists and breeders. Seed priming has become established as one of the practical approaches that can alleviate the negative impact of many environmental stresses and improve the germination and overall performance of crops. Hormopriming using different plant growth regulators has been widely demonstrated as effective, but information about using cytokinins (CKs) as priming agents is limited to only a few studies using kinetin or 6-benzylaminopurine (BAP). Moreover, the mode of action of these compounds in improving seed and plant fitness through priming has not yet been studied. For many years, BAP has been one of the CKs most commonly applied exogenously to plants to delay senescence and reduce the impact of stress. However, rapid endogenous N9-glucosylation of BAP can result in negative effects. This can be suppressed by hydroxylation of the benzyl ring or by appropriate N9 purine substitution. Replacement of the 2′ or 3′ hydroxyl groups of a nucleoside with a fluorine atom has shown promising results in drug research and biochemistry as a means of enhancing biological activity and increasing chemical or metabolic stability. Here, we show that the application of this chemical modification in four new N9-substituted CK derivatives with a fluorinated carbohydrate moiety improved the antisenescence properties of CKs. Besides, detailed phenotypical analysis of the growth and development of Arabidopsis plants primed with the new CK analogs over a broad concentration range and under various environmental conditions revealed that they improve growth regulation and antistress activity. Seed priming with, for example, 6-(3-hydroxybenzylamino)-2′-deoxy-2′-fluoro-9-(β)-D-arabinofuranosylpurine promoted plant growth under control conditions and alleviated the negative effects of the salt and osmotic stress. The mode of action of this hormopriming and its effect on plant metabolism were further analyzed through quantification of the endogenous levels of phytohormones such as CKs, auxins and abscisic acid, and the results are discussed.

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S-Adenosylhomocysteine hydrolase of the protozoan parasite Trichomonas vaginalis: Potent inhibitory activity of 9-(2-deoxy-2-fluoro-β,d-arabinofuranosyl)adenine

Cited by 11 publications

References 23 publications

Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter

Comprehensive characterization of purine and pyrimidine transport activities in Trichomonas vaginalis and functional cloning of a trichomonad nucleoside transporter

Deazapurine Nucleoside Analogues for the Treatment of Trichomonas vaginalis

Hormopriming to Mitigate Abiotic Stress Effects: A Case Study of N9-Substituted Cytokinin Derivatives With a Fluorinated Carbohydrate Moiety

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