Practical synthesis of 1′-substituted Tubercidin C-nucleoside analogs

Metobo, Sammy; Xu, Jie; Saunders, Oliver L.; Butler, Thomas; Aktoudianakis, Evangelos; Cho, Aesop; Kim, Choung U.

doi:10.1016/j.tetlet.2011.11.055

Cited by 43 publications

(54 citation statements)

References 19 publications

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“…Along with the compounds shown in Schemes 1 and 2, two additional compounds, namely the 9-deaza-2′-deoxynucleosides 11 and 12 were tested owing to past 1–7,47–57 and recent 58 interest in the pharmacological properties of 9-deazanucleosides. The syntheses of the compounds shown in Figure 4 have been previously reported by our group but their antiproliferative properties had not yet been evaluated.…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

Temburnikar¹,

Ross²,

Wilson³

et al. 2015

Bioorganic & Medicinal Chemistry

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In vitro evaluation of the halogenated pyrrolo[3,2-d]pyrimidines identified antiproliferative activities in compounds 1 and 2 against four different cancer cell lines. Upon screening of a series of pyrrolo[3, 2-d]pyrimidines, the 2,4-Cl compound 1 was found to exhibit antiproliferative activity at low micromolar concentrations. Introduction of iodine at C7 resulted in significant enhancement of potency by reducing the IC50 into sub-micromolar levels, thereby suggesting the importance of a halogen at C7. This finding was further supported by an increased antiproliferative effect for 4 as compared to 3. Cell-cycle and apoptosis studies conducted on the two potent compounds 1 and 2 showed differences in their cytotoxic mechanisms in triple negative breast cancer MDA-MB-231 cells, wherein compound 1 induced cells to accumulate at the G2/M stage with little evidence of apoptotic death. In contrast, compound 2 robustly induced apoptosis with concomitant G2/M cell cycle arrest in this cell model.

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Section: Resultsmentioning

confidence: 99%

Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

Temburnikar¹,

Ross²,

Wilson³

et al. 2015

Bioorganic & Medicinal Chemistry

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“…The development process of Remdesivir took several years. Its structure design of the ribose skeleton takes into account the efficient combination with the RdRP, as well as better chemical stability (4,5,6,13,14). At present, there is still no systematic study on the reproductive toxicity of GS-5734.…”

Section: Discussionmentioning

confidence: 99%

“…It has been proved purinergic signaling is involved in hormone secretion, penile erection, sperm motility and capacitation, and mucous production. As a similar competitor to adenosine triphosphate (ATP), GS-5734 can competitively combine and inhibit RNA dependent RNA polymerase (RdRP) of many RNA viruses, including Fibrovirus (Ebola), Coronavirus (COVID-19), Flaviviridae (Hepatitis C virus), thereby inhibiting virus replication (4)(5)(6). In 2020, Remdesivir as a novel and promising medicine for COVID-2019 has gained Orphan Drug designation from FDA.…”

Section: Introductionmentioning

confidence: 99%

A preliminary study on the reproductive toxicity of GS-5734 on male mice

Fan

Luo

Zhao

et al. 2020

Preprint

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Background: GS-5734 as a novel and promising medicine for COVID-2019, its biological impact on the mammalian reproductive system has not been systematically studied. The aim of this study was to evaluate the effects of GS-5734 on sperm parameters and spermatogenesis in mice. Materials and Methods:In this study, GS-5734 was synthesized according to the report. 28 adult male mice were randomly segregated into four groups (n=7 for each group). The group 1 was set as the control group, the group 1, 2, 3 and 4 were administered with GS-5734 at a daily dose of 0, 10, 50, 150 μ g/mouse respectively, by intraperitoneal injection for 10 days. On the 7th day after the last injection, the testes and cauda epididymides were collected for HE staining and sperm concentration, motility, morphology analysis. Results:The results indicated that after treated with GS-5734, the total sperm count and motile sperm rate showed downward trends, the abnormal sperm rate showed an increasing trend. As compared with the control group, GS-5734 at a daily dose of 150 μ g/mouse caused a significant decrease in sperm concentration and motility, and a significant increased of abnormal sperm rate; the 50 μ g/mouse drug treatment lead to a significant decrease in sperm motility and an increase in abnormal sperm rate. The HE staining of testicular and epididymal tissues showed that the spermatogenesis of mice was significantly deteriorated with the increasing dosage of GS-5734, especially in the 150 μ g/mouse group. Conclusion:Our findings suggest that a high dosage of GS-5734 may induce testicular toxicity and result in deterioration of sperm parameters in mice. More investigation on the reproductive toxicity of GS-5734 is required.

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“…In initial attempts, 4‐aza‐7‐deaza‐9‐bromo‐adenine 8 , which was synthesized according to a published procedure, was selected as coupling partner (Scheme ). The hydroxy groups of ribolactone 6 were fully protected as benzyl ethers using benzyl 2,2,2‐trichloroacetimidate under acidic conditions . Nucleophilic addition of the lithium salt of heterocycle 8 to tribenzyl lactone 7 afforded compound 9 as an anomeric mixture.…”

Section: Resultsmentioning

confidence: 99%

“…In our hands, this reaction proceeded with yields between 10 and 30 %, which are lower than the reported yield of 38 %. A literature report indicates that the transient protection of the exocyclic amino group as its stabase adduct led to an improvement of the yield to 60 % …”

Section: Resultsmentioning

confidence: 99%

Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose, and 2′,3′‐Dideoxyribose Sugar Moiety

Lescrinier

Groaz

et al. 2017

ChemMedChem

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The synthesis of hitherto unknown pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4‐aza‐7,9‐dideazaadenine. In addition, pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides bearing a 2′‐deoxy‐, 2′,3′‐dideoxy‐, and 2′,3′‐dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1‐f][1,2,4]triazine C‐ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines.

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Practical synthesis of 1′-substituted Tubercidin C-nucleoside analogs

Cited by 43 publications

References 19 publications

Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

Antiproliferative activities of halogenated pyrrolo[3,2-d]pyrimidines

A preliminary study on the reproductive toxicity of GS-5734 on male mice

Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose, and 2′,3′‐Dideoxyribose Sugar Moiety

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