The first general synthesis of 2-<i>C</i>-(β-<scp>d</scp>-glycopyranosyl)pyrimidines and their evaluation as inhibitors of some glycoenzymes

Szennyes, Eszter; Bokor, Éva; Langer, Peter; Gyémánt, Gyöngyi; Docsa, Tibor; Sipos, Attila; Somsák, László

doi:10.1039/c8nj04035d

Cited by 10 publications

(23 citation statements)

References 42 publications

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“…The new unprotected compounds 11 and 18 were tested as inhibitors of some glycoenzymes. Similarly to the previously tested 2-C-glucopyranosyl pyrimidines (I and II in Figure 1) [17], none of them exhibited inhibition against rabbit muscle glycogen phosphorylase b (rmGPb) and almond βglucosidase.…”

Section: Enzyme Inhibition Studiesmentioning

confidence: 72%

“…While 2-(β-D-glucopyranosyl)-6-phenylpyrimidin-4(3H)-one 19 was earlier shown to be a submillimolar inhibitor of yeast α-glucosidase (IC 50 = 0.7 mM) [17], the new analogs 11 had negligible effects against this enzyme. Table 3.…”

Section: Enzyme Inhibition Studiesmentioning

confidence: 98%

“…In order to avoid the critical deprotection in the last step of the synthesis, the preparation of the unprotected pyrimidines 11 was also examined in a reversed sequence, wherein the formamidine salt 2, obtained from 1 by hydrogenolytic O-debenzylation [17], was cyclized with the corresponding methylenemalonic acid derivatives 3-7 ( Table 1). The ring-closure of 2 with compounds 3-7 proceeded similarly to that of amidine salt 1, providing each target test compound 11a-f in moderate to good yields.…”

Section: Synthesesmentioning

confidence: 99%

“…The inhibition of rmGPb by the test compounds was investigated with a maximal inhibitory concentration of 625 µM by applying a general protocol described earlier [17,27].…”

Section: Enzyme Assaysmentioning

confidence: 99%

“…Recently, as part of a systematic study on the syntheses of 2-C-glycopyranosyl pyrimidines (e.g., I and II in Figure 1), we published their first general synthesis from the corresponding O-perbenzylated (1) or O-unprotected C-glucopyranosyl formamidines (2) as well as in a one-pot three-step transformation of O-peracylated glycopyranosyl cyanides [17]. Some members of I and II exhibited moderate inhibition of some glycosidase enzymes [17], however, each proved inactive against glycogen phosphorylase [17]. Although these biological effects are not outstanding, these are the first investigations to reveal potential utilities of this novel compound class.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of New Series of 2-C-(β-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes

et al. 2020

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Despite the substantial interest in C-glycosyl heterocycles as mimetics of biologically active native glycans, the appearance of C-glycopyranosyl derivatives of six-membered heterocycles, both in synthetic and biological contexts, is rather scarce. As part of our ongoing research program aimed at preparing hitherto barely known 2-C-glycopyranosyl pyrimidines, the goal of the present study was to synthesize new 5-mono- and multiply substituted derivatives of this compound class. Thus, 2-C-(β-D-glucopyranosyl)-5,6-disubstituted-pyrimidin-4(3H)-ones and 4-amino-2-C-(β-D-glucopyranosyl)-5,6-disubstituted-pyrimidines were prepared by base-mediated cyclocondensations of O-perbenzylated and O-unprotected C-(β-D-glucopyranosyl) formamidine hydrochlorides with methylenemalonic acid derivatives. The 2-C-(β-D-glucopyranosyl)-5-substituted-pyrimidines were obtained from the same amidine precursors upon treatment with vinamidinium salts. The deprotected derivatives of these pyrimidines were tested as inhibitors of some glycoenzymes. None of them showed inhibitory activity towards glycogen phosphorylase and α- and β-glucosidase enzymes, but some members of the sets exhibited moderate inhibition against bovine liver β-galactosidase.

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Section: Enzyme Inhibition Studiesmentioning

confidence: 72%

Section: Enzyme Inhibition Studiesmentioning

confidence: 98%

Section: Synthesesmentioning

confidence: 99%

“…The inhibition of rmGPb by the test compounds was investigated with a maximal inhibitory concentration of 625 µM by applying a general protocol described earlier [17,27].…”

Section: Enzyme Assaysmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of New Series of 2-C-(β-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes

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In the Search of Glycoside-Based Molecules as Antidiabetic Agents

et al. 2019

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This review is an effort to summarize recent developments in synthesis of O -glycosides and N -, C -glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the O -glycosides used in the treatment of diabetes are presented, followed by the N -glycosides and finally the C -glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order. C -Glycosyl compounds mimicking O -glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various C -glycosides. Also N -glycosides such as N -(β- d -glucopyranosyl)-amides, N -(β- d -glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect. 5 . In Sect. 6 , biological mechanisms of action of the glycosides and patents of marketed drugs are described.

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N- and C-Glycopyranosyl heterocycles as glycogen phosphorylase inhibitors

Bokor

2020

Recent Trends in Carbohydrate Chemistry

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The first general synthesis of 2-C-(β-d-glycopyranosyl)pyrimidines and their evaluation as inhibitors of some glycoenzymes

Abstract: The first systematic study on the synthesis of 2-C-(β-d-glycopyranosyl)pyrimidines either from amidine A or glycosyl cyanides B and 1,3-dicarbonyl compounds.

Cited by 10 publications

References 42 publications

Synthesis of New Series of 2-C-(β-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes

Synthesis of New Series of 2-C-(β-D-glucopyranosyl)-Pyrimidines and Their Evaluation as Inhibitors of Some Glycoenzymes

In the Search of Glycoside-Based Molecules as Antidiabetic Agents

N- and C-Glycopyranosyl heterocycles as glycogen phosphorylase inhibitors

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