Revisiting tubercidin against kinetoplastid parasites: Aromatic substitutions at position 7 improve activity and reduce toxicity

Hulpia, Fabian; Campagnaro, Gustavo Daniel; Scortichini, Mirko; Hecke, Kristof Van; Maes, Louis; Koning, Harry P. de; Caljon, Guy; Calenbergh, Serge Van

doi:10.1016/j.ejmech.2018.12.050

Cited by 43 publications

(102 citation statements)

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“…Based on the reported activity of cordycepin and tubercidin, and taking into account our recently reported tubercidin derivatives 25 , a small series of 2′- and 3′-deoxytubercidin analogues was synthesized (Supplementary Methods) and evaluated in vitro against T. brucei spp. (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…For decades nucleoside (and nucleobase) analogues have been successfully used in the clinic, particularly for the treatment of viral infections and cancer, which is evidenced by the more than 40 chemical entities from this compound class that are Food and Drug Administration approved at the present date 34,35 . Their utilization in the treatment of parasitic infections, however, is currently limited to the occasional use of allopurinol against canine leishmaniasis 36 , although many other purine and pyrimidine analogues have been tested for their antitrypanosomal and leishmanicidal effects, most prominently against T. brucei 14,17,18,21,25,37 . Using nucleoside analogues as chemotherapeutic agents against HAT potentially benefits from the inherently higher likelihood of crossing the BBB than for most other water-soluble compounds 22 , thus enabling their use in the neurological stage of the disease 1 .…”

Section: Discussionmentioning

confidence: 99%

“…Inspired by the activity of tubercidin against T. brucei spp., we recently explored a series of 7-substituted tubercidin analogues and identified analogues displaying promising in vitro activity against kinetoplastid parasites 25 . In an attempt to further increase the antitrypanosomal activity, we set out to investigate the effect of modifying the sugar part of tubercidin and its 7-substituted analogues.…”

Section: Introductionmentioning

confidence: 99%

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Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness

et al. 2019

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African trypanosomiasis is a disease caused by Trypanosoma brucei parasites with limited treatment options. Trypanosoma is unable to synthesize purines de novo and relies solely on their uptake and interconversion from the host, constituting purine nucleoside analogues a potential source of antitrypanosomal agents. Here we combine structural elements from known trypanocidal nucleoside analogues to develop a series of 3’-deoxy-7-deazaadenosine nucleosides, and investigate their effects against African trypanosomes. 3’-Deoxytubercidin is a highly potent trypanocide in vitro and displays curative activity in animal models of acute and CNS-stage disease, even at low doses and oral administration. Whole-genome RNAi screening reveals that the P2 nucleoside transporter and adenosine kinase are involved in the uptake and activation, respectively, of this analogue. This is confirmed by P1 and P2 transporter assays and nucleotide pool analysis. 3’-Deoxytubercidin is a promising lead to treat late-stage sleeping sickness.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

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Section: Introductionmentioning

confidence: 99%

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Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness

et al. 2019

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“…4, Figure 1) as potent and selective anti-T. brucei agents. 18 Additionally, we discovered that the combination of the 3'deoxyribuforanose sugar of cordycepin with the 7-deazapurine base of tubercidin resulted in highly potent 'hybrid' compounds, of which 5 was able to cure CNS-stage T. b. brucei infections in mice by oral dosing, marking it a promising lead compound for further development. 19 In the present study, we describe our efforts to systematically investigate the structure-activity-relationship (SAR) of these 3'deoxy-7-deazapurine nucleoside analogues and identify several potent and selective back-up derivatives that are ready for further evaluation in animal models of HAT.…”

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Structure–Activity Relationship Exploration of 3′-Deoxy-7-deazapurine Nucleoside Analogues as Anti-Trypanosoma brucei Agents

et al. 2020

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Human African trypanosomiasis is a neglected tropical disease caused by Trypanosoma brucei parasites. These protists are unable to produce the purine ring, making them vulnerable to the effects of purine nucleoside analogues. Starting from 3'-deoxytubercidin 5, a lead compound with activity against central nervous stage human African trypanosomiasis, we investigate the structure-activity relationship of the purine and ribofuranose ring. The purine ring tolerated only modifications at C7, while from the many alterations of the 3'-deoxyribofuranosyl moiety only the arabino analogue 48 showed pronounced antitrypanosomal activity. Profiling of the most potent analogues against resistant T. brucei strains (resistant to pentamidine, diminazene and isometamidium) showed reduced dependence on uptake mediated by the P2 aminopurine transporter compared to 5. The introduction of a 7-substituent confers increased affinity for the P1 nucleoside transporter up to 10-fold, while generally retaining high affinity for P2. Four of the most promising analogues were found to be metabolically stable, earmarking them suitable back-up analogues for lead 5.

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“…Since then, 7-deazapurine has been recognized as a privileged scaffold in developing new antitumor and antiviral nucleosides [ 8 ]. Consequently, many 7-deazapurine nucleosides have been synthesized and their biological activities have been screened in the past 50 years [ 9 , 10 , 11 ]. Among them, several promising lead compounds have been discovered [ 12 , 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

First Total Synthesis of 5′-O-α-d-Glucopyranosyl Tubercidin

Ouyang¹,

Huang²,

Yang³

et al. 2020

Marine Drugs

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The first total synthesis of 5′-O-α-d-glucopyranosyl tubercidin was successfully developed. It is a structurally unique disaccharide 7-deazapurine nucleoside exhibiting fungicidal activity, and was isolated from blue-green algae. The total synthesis was accomplished in eight steps with 27% overall yield from commercially available 1-O-acetyl-2,3,5-tri-O-benzoyl-β-d-ribose. The key step involves stereoselective α-O-glycosylation of the corresponding 7-bromo-6-chloro-2′,3′-O-isopropylidene-β-d-tubercidin with 2,3,4,6-tetra-O-benzyl-glucopyranosyl trichloroacetimidate. All spectra are in accordance with the reported data for natural 5′-O-α-d-glucopyranosyl tubercidin. Meanwhile, 5′-O-β-d-glucopyranosyl tubercidin was also prepared using the same strategy.

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Revisiting tubercidin against kinetoplastid parasites: Aromatic substitutions at position 7 improve activity and reduce toxicity

Abstract: There may be differences between this version and the published version. You are advised to consult the publisher's version if you wish to cite from it.

Cited by 43 publications

References 82 publications

Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness

Combining tubercidin and cordycepin scaffolds results in highly active candidates to treat late-stage sleeping sickness

Structure–Activity Relationship Exploration of 3′-Deoxy-7-deazapurine Nucleoside Analogues as Anti-Trypanosoma brucei Agents

First Total Synthesis of 5′-O-α-d-Glucopyranosyl Tubercidin

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