Synthesis, self-assembly behaviours and multivalent glycosidase inhibition effects of a deoxynojirimycin modified perylene bisimide derivative

Li, Juanjuan; Wang, Ke-Rang; Li, Renfeng; Yang, Jian-Xing; Li, Min; Cao, Ziping; Li, Xiaoliu

doi:10.1039/c8tb03122c

Cited by 16 publications

(10 citation statements)

References 46 publications

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“…More recently, the acquisition and solving of X-ray structures of two complexes between enzymes and a multimeric inhibitor allowed to draw explanations for the strongest inhibitory multivalent effect obtained to date with cluster 1e [50], or for an exceptional selectivity [49], and opened the way for a new area where rational design of multivalent inhibitors will be possible. Moreover, multivalent inhibitors have demonstrated their therapeutic potential and have proven to be able to cross membranes by in vitro [52,53] and in vivo [54] experiments. In this project, we wanted to build new multivalent constructs by associating the advantages of calixarene scaffolds with those of 1-deoxynojirimycin (DNJ), the inhitope that has led to the best inhibitory multivalent effect reported so far [44].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

et al. 2020

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A set of 6- to 24-valent clusters was constructed with terminal deoxynojirimycin (DNJ) inhibitory heads through C6 or C9 linkers by way of Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions between mono- or trivalent azido-armed iminosugars and calix[8]arene scaffolds differing in their valency and their rigidity but not in their size. The power of multivalency to upgrade the inhibition potency of the weak DNJ inhibitor (monovalent DNJ Ki being at 322 and 188 µM for C6 or C9 linkers, respectively) was evaluated on the model glycosidase Jack Bean α-mannosidase (JBα-man). Although for the clusters with the shorter C6 linker the rigidity of the scaffold was essential, these parameters had no influence for clusters with C9 chains: all of them showed rather good relative affinity enhancements per inhibitory epitopes between 70 and 160 highlighting the sound combination of the calix[8]arene core and the long alkyl arms. Preliminary docking studies were performed to get insights into the preferred binding modes.

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Section: Introductionmentioning

confidence: 99%

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

et al. 2020

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“…The first self-assembled multivalent glycosidase inhibitor was constructed with glycopolypeptide derivatives by Lecommandoux and co-workers, and it exhibited a 206-fold higher inhibition effect against α-mannosidase (jack bean) than the monovalent agent. Recently, we developed self-assembled multivalent glycosidase inhibitors based on perylene–deoxynojirimycin and amphiphilic fatty acid–deoxynojirimycin , conjugates, which showed potent multivalent glycosidase inhibition effects against α-mannosidase (jack bean) with K i values of 38 nm and 0.11 μM, respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, especially against α-mannosidase (jack bean), further applications and research directions need to be developed in the future . Notably, we first evaluated the hypoglycemic effects of self-assembled multivalent glycosidase inhibitors in mice, which opened a new avenue of research on novel antihyperglycemic agents. ,, However, there are some problems that need to be solved in regard to multivalent antihyperglycemic agents, such as the relationship between the inhibition of glycosidase activity and hypoglycemic effects and the relationship between the self-assembly properties and the inhibition of glycosidase activity or the hypoglycemic effects.…”

Section: Introductionmentioning

confidence: 99%

Positional Isomeric Effects on the Optical Properties, Multivalent Glycosidase Inhibition Effect, and Hypoglycemic Effect of Perylene Bisimide–deoxynojirimycin Conjugates

Yang

Liu

et al. 2021

J. Med. Chem.

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Although multivalent glycosidase inhibitors have shown enhanced glycosidase inhibition activities, further applications and research directions need to be developed in the future. In this paper, two positional isomeric perylene bisimide derivatives (PBI-4DNJ-1 and PBI-4DNJ-2) with 1-deoxynojirimycin conjugated were synthesized. Furthermore, PBI-4DNJ-1 and PBI-4DNJ-2 showed positional isomeric effects on the optical properties, self-assembly behaviors, glycosidase inhibition activities, and hypoglycemic effects. Importantly, PBI-4DNJ-1 exhibited potent hypoglycemic effects in mice with 41.33 ± 2.84 and 37.45 ± 3.94% decreases in blood glucose at 15 and 30 min, respectively. The molecular docking results showed that the active fragment of PBI-4DNJ-1 has the highest binding energy (9.649 kcal/mol) and the highest total hydrogen bond energy (62.83 kJ/mol), which were related to the positional isomeric effect on the hypoglycemic effect in mice. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

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“…酶抑制剂，其对 α-甘露糖苷酶的抑制作用比单体高 206 倍。我们课题组在基于苝酰亚胺-野尻霉素类 [17] 和脂肪胺-野尻霉素 [18,19] 两亲类自组装多效价糖苷酶抑制剂方面做了系列工作，并将其首次用于小鼠体内降糖研究，实现了 41%的降糖效果 [20] 。虽然，多效价糖苷酶抑制剂的研究已有十几年时间，取得了丰硕研究成果。然而，一些关键科学问题需要解决，一是如何有效构筑多效价糖苷酶抑制剂分子；二是如何有效提高其对 α-糖苷酶的抑制活性 [21]…”

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Self-assembled multivalent glycosidase inhibition effect based on perylene monoimide-deoxynojirimycin conjugates

Li¹,

Yang²,

Zhang³

et al. 2021

Sci. Sin.-Chim

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Diabetes mellitus is a serious and chronic disease. Recently, multivalent glycosidase inhibitors were found and rapidly developed. The key element for construction of multivalent glycosidase inhibitor remained a large challenge. In this paper, a perylene monoimide derivative (PMI-DNJ) with 1-deoxynojirimycin conjugated was synthesized. Furthermore, its self-assembly behaviors and glycosidase inhibition effects were studied. PMI-DNJ showed very good glycosidase inhibition activity against α-mannosidase (jack bean) with a Ki value of 1.41 μM, increased approximately 24-fold and 65-fold compared with the control drugs (miglitol and DNJ-1). Moreover, the Ki value of PMI-DNJ against α-glucosidase was 10.98 μM, increased approximately 1.88-fold and 5.6-fold compared with the control drugs (miglitol and DNJ-1). In addition, PMI-DNJ exhibited potent hypoglycemic effects in mice with 27.36% and 30.08 % decreases in blood glucose under the drug dose of 0.5 and 1.0 mg/kg. This work introduced a new means to develop antihyperglycemic agents in the field of multivalent glycomimetics.

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Synthesis, self-assembly behaviours and multivalent glycosidase inhibition effects of a deoxynojirimycin modified perylene bisimide derivative

Abstract: A self-assembled multivalent glycosidase inhibitor based on perylene bisimide-deoxynojirimycin conjugates was constructed, inhibited α-mannosidase and exhibited a Ki value of 38 nM, increased approximately 2763-fold compared with the control drug (miglitol).

Cited by 16 publications

References 46 publications

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

Synthesis and Glycosidase Inhibition Properties of Calix[8]arene-Based Iminosugar Click Clusters

Positional Isomeric Effects on the Optical Properties, Multivalent Glycosidase Inhibition Effect, and Hypoglycemic Effect of Perylene Bisimide–deoxynojirimycin Conjugates

Self-assembled multivalent glycosidase inhibition effect based on perylene monoimide-deoxynojirimycin conjugates

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