Abstract:The design and synthesis of a glucose-based acridone derivative (GLAC), a potent inhibitor of glycogen phosphorylase (GP) are described. GLAC is the first inhibitor of glycogen phosphorylase, the electronic absorption properties of which are clearly distinguishable from those of the enzyme. This allows probing subtle interactions in the catalytic site. The GLAC absorption spectra, associated with X-ray crystallography and quantum chemistry calculations, reveal that part of the catalytic site of GP behaves as a… Show more
“…The new compounds, nevertheless, exhibit a rather low inhibition profile compared with the known spirohydantoin derivative of glucopyranose [5] and other known strong catalytic site inhibitors of RMGPb. [29,30] We have established previously that anti is the desirable conformation of the pyrimidine ring at the anomeric position of -D-glucose leading to strong inhibition, [30] and the current results confirm this finding. Anomeric spironucleosides are rigid structures and given that they possess the correct conformation, they are expected to bind strongly to the catalytic site of GP.…”
Glycogen phosphorylase (GP) has been a target for compounds, inhibitors of GP that might prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production from the liver, in the case of type 2 diabetes. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and possess important biological function. We have successfully applied the Suárez radical methodology to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not been previously constructed via a radical pathway, starting from 6-hydroxymethyl-β-D-glucopyranosyluracil. We have shown that in the rigid pyranosyl conformation the required [1,5]-radical translocation is a minor process. The stereochemistry of the spirocycles obtained were unequivocally determined based on the chemical shifts of key sugar protons in the 1H NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.
“…The new compounds, nevertheless, exhibit a rather low inhibition profile compared with the known spirohydantoin derivative of glucopyranose [5] and other known strong catalytic site inhibitors of RMGPb. [29,30] We have established previously that anti is the desirable conformation of the pyrimidine ring at the anomeric position of -D-glucose leading to strong inhibition, [30] and the current results confirm this finding. Anomeric spironucleosides are rigid structures and given that they possess the correct conformation, they are expected to bind strongly to the catalytic site of GP.…”
Glycogen phosphorylase (GP) has been a target for compounds, inhibitors of GP that might prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production from the liver, in the case of type 2 diabetes. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and possess important biological function. We have successfully applied the Suárez radical methodology to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not been previously constructed via a radical pathway, starting from 6-hydroxymethyl-β-D-glucopyranosyluracil. We have shown that in the rigid pyranosyl conformation the required [1,5]-radical translocation is a minor process. The stereochemistry of the spirocycles obtained were unequivocally determined based on the chemical shifts of key sugar protons in the 1H NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.
“…The new compounds, nevertheless, exhibit a rather low inhibition profile compared with the known spirohydantoin derivative of glucopyranose [5] and other known strong catalytic site inhibitors of RMGP b [7,30]. We established previously that anti is the desirable conformation of the pyrimidine ring at the anomeric position of β- d -glucose leading to strong inhibition [7], and the current results confirm this finding. Anomeric spironucleosides are rigid structures and, given that they possess the correct conformation, are expected to bind strongly to the catalytic site of GP.…”
Section: Discussionsupporting
confidence: 82%
“…To this end, a number of attempts to synthesize more potent inhibitors were made leading to other spiro-heterocycles that exhibited stronger affinity for RMGP b [6]. Similar studies in our laboratory led to N 4 -aryl- N 1 -(β- d -glucopyranosyl)cytidine nucleosides which exhibit RMGP b inhibition in the nanomolar range [7].…”
In the case of type 2 diabetes, inhibitors of glycogen phosphorylase (GP) may prevent unwanted glycogenolysis under high glucose conditions and thus aim at the reduction of excessive glucose production by the liver. Anomeric spironucleosides, such as hydantocidin, present a rich synthetic chemistry and important biological function (e.g., inhibition of GP). For this study, the Suárez radical methodology was successfully applied to synthesize the first example of a 1,6-dioxa-4-azaspiro[4.5]decane system, not previously constructed via a radical pathway, starting from 6-hydroxymethyl-β-d-glucopyranosyluracil. It was shown that, in the rigid pyranosyl conformation, the required [1,5]-radical translocation was a minor process. The stereochemistry of the spirocycles obtained was unequivocally determined based on the chemical shifts of key sugar protons in the 1H-NMR spectra. The two spirocycles were found to be modest inhibitors of RMGPb.
“…A key point for the design of efficient drugs is the characterization of the interactions governing its binding to the enzyme. In 2017, Mamais et al designed and prepared a glucose-based acridone derivative (GLAC), which is a potent inhibitor of GP and it allows probing subtle interactions in catalytic site [ 37 ]. The design of a catalytic site inhibitor was based on C-4 modification of β- d -glucopyranosyluracil and introducing of flat aromatic substituent, which can increase the binding affinity in the β-channel.…”
Section: N
-Glycosides As Antidiabetic Agentsmentioning
confidence: 99%
“…Authors reveal that the part of the catalytic site of GP behaves as a highly basic environment in which GLAC 87 exists as a bis-anion. Authors reassumed that solvent structure of GLAC and the water-bridged hydrogen bonding interactions formed with the catalytic site residues in the β-channel are responsible for the observed inhibition potency [ 37 ]. Scheme 14 Synthesis of GLAC 87 (N 1 -( β - d -glucopyranosyl)-N 4 -[2-acridin-9(10 H )-onyl]-cytosine) [ 37 ] …”
Section: N
-Glycosides As Antidiabetic Agentsmentioning
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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