Enhanced Radical-Scavenging Activity of a Planar Catechin Analogue

Fukuhara, Kiyoshi; Nakanishi, Ikuo; Kansui, Hisao; Sugiyama, Etsuko; Kimura, Mitsuhiro; Shimada, Tomokazu; Urano, Shiro; Yamaguchi, Kentaro; Miyata, Naoki

doi:10.1021/ja0178259

Cited by 89 publications

(82 citation statements)

References 25 publications

(17 reference statements)

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“…The little improvement moving from 11h to 12h can be rationalized by considering for the former the additional effect of the conjugated double bond. 30 More of our efforts were devoted to better understanding the role of the substitution and the sulfur atom on the "tocopherollike" antioxidant mechanism played by the A and C rings.…”

Section: Antioxidant Activitymentioning

confidence: 99%

Synthesis and “double-faced” antioxidant activity of polyhydroxylated 4-thiaflavans

et al. 2005

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A simple synthetic methodology, based on the inverse electron demand hetero Diels-Alder reaction of electron-poor dienic o-thioquinones with electron-rich styrenes used as dienophiles, allowed the preparation of several polyhydroxylated 4-thiaflavans. Such compounds, as a function of the nature and position of the substituents on the aromatic rings, as well as of the oxidation state of the sulfur atom, are able to behave in vitro as efficient antioxidants mimicking the action of catechol containing flavonoids or/and tocopherols. The possibility of joining together the potentialities of two relevant families of natural polyphenolic antioxidants appears particularly appealing since an efficient protection against free radicals and other reactive oxygen species (ROS) depends in vivo upon the synergic action of different antioxidant derivatives.

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Section: Antioxidant Activitymentioning

confidence: 99%

Synthesis and “double-faced” antioxidant activity of polyhydroxylated 4-thiaflavans

et al. 2005

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“…Typically, CA and 1.2 equivalents of acetone in THF were treated with 1.2 equivalents of TMSOTf at -59 C to form the PCA in 3 hours. The planarity of PCA was conˆrmed by single-crystal X-ray crystallography (14). X-ray analysis also showed that the stereochemistry of 3-H on ring C was maintained throughout the reaction without any acid-catalyzed racemization.…”

Section: Synthesismentioning

confidence: 86%

A Planar Catechin Analogue as a New Type of Synthetic Antioxidant

Fukuhara¹

2006

Genes and Environment

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The protective role of antioxidants against free-radical associated diseases has been widely studied, leading to the development of new types of antioxidants to remove reactive oxygen species such as O 2 -and  OH. We synthesized a new type of synthetic antioxidant in which the catechol (B ring) and chroman moieties (AC ring) within the (＋)-catechin (CA) structure were constrained to be planar. As compared with CA, planar catechin (PCA) showed strong radical scavenging activities towards both galvinoxyl and cumylperoxyl radicals. Reduced prooxidant activity was also observed, consistent with the dianion form of PCA being weaker at generating O 2 -than the dianion form of CA. PCA completely inhibited DNA-strand scission induced by the Fenton reaction, whereas CA exhibited not only antioxidant properties but also prooxidant properties consistent with enhanced DNA strand cleavage. As compared with hydrophilic CA, the lipophilicity of PCA due to its planarity may aid in penetration of these antioxidant molecules past the cell membrane. Further development of planar PCA may be a favorable approach towards new clinically useful antioxidants for the treatment of free-radical associated diseases.

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“…DNA strand scission in the super coiled pBR322DNA was induced by ROS in the presence of p benzoquinone or p benzoquinone imine, metal ion, and NADH. 17) Compound 24 induced DNA strand breakage condition in the above conditions (data not shown). We suggest that ROS generated enzyme inhibition might be a new approach for the development of an enzyme inhibitor.…”

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confidence: 79%

“…We reasoned that the enzymatic liberation of the aglycon from compounds 18 and 24 might be followed by the ejection of a sulfinate anion with the concomitant formation of p benzoquinone and p benzoquinone imine, which would then generate ROS in the enzyme active site, leading to enzyme deactivation. 16,17) Therefore, the effects of compounds 18 and 24 on ROS mediated DNA breakage were investigated. DNA strand scission in the super coiled pBR322DNA was induced by ROS in the presence of p benzoquinone or p benzoquinone imine, metal ion, and NADH.…”

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confidence: 99%

N-Linked Oligosaccharide Processing Enzymes as Molecular Targets for Drug Discovery

Hakamata¹,

Muroi²,

Nishio³

et al. 2006

J. Appl. Glycosci.

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α Glucosidases (EC 3.2.1.20) are also exo acting carbohydrases, catalyzing the release of α D glucopyranose from the non reducing ends of various substrates, 1,2) and on the basis of amino acid sequence similarities, α glucosidases are classified into two families, family 13 and family 31. 3,4) Endoplasmic reticulum (ER) glucosidases, glucosidase I (EC 3.2.1.106) and glucosidase II (EC 3.2.1.84), are key enzymes in the biosynthesis of asparagine linked oligosaccharides that catalyze the first processing event after the transfer of Glc3Man9GlcNAc2 to proteins. These enzymes are a target for inhibition by anti viral agents that interfere with the formation of essential glycoproteins required in viral assembly, secretion and infectivity.5) Many papers reported that inhibitors of α glucosidases are potential therapeutics for the treatment of such diseases as viral diseases, cancer and diabetes. 5,6) However, many screenings of α glucosidase inhibitors did not use enzymes from target tissues or organs. We think that the molecular recognitions of three kinds of glucosidases (family 13, family 31 α glucosidases and ER glucosidases) are different. Therefore, the glycon and aglycon specificity profiling of glucosidases has been an important approach for the research of glucosidase inhibitors.In this research, we first describe the glycon and aglycon specificity profiling of glucosidases using small molecules as probes. Next, compounds designed and synthesized as glucosidase inhibitor candidates were evaluated with regard to their ability to inhibit three kinds of glucosidases. Finally, the glucosidase inhibitor candidates were tested for their anti viral activities in a cell culture system.Glycon specificity profiling of glucosidases using chemically modified substrates. Chemically modified substrates are effective methods in the study of substrate specificity profiling. We have applied this approach to family 13 and family 31 α glucosidases, 7 10) ER glucosidases, 11,12) α galactosidases 8,13) and α mannosidases 8,14) using partially substituted monosaccharides. We used all of the monodeoxy analogs of p nitrophenyl α D glucopyranoside (PNP α Glc) 1 4 (Fig. 1) as chemically modified substrates for glycon specificity profiling. We investigated the hydrolytic activities of family 13 and family 31 α glucosidases and ER glucosidase II of PNP α Glc and its deoxy derivatives 1 4, and checked the inhibitory activities of ER glucosidase I of PNP α Glc and probes 1 4, so that PNP α Glc was not a substrate for ER glucosidase I. These results are shown in Table 1. 11,12) Clearly, of the four deoxy derivatives of PNP α Glc 1 4, family 31 α glucosidases and ER glucosidase II hydrolyzed the 2 deoxy glucopyranoside (1); its activity with 1 appeared to be substantially higher than that with PNP α Glc. Kinetic studies of the hydrolysis of PNP α Glc, 1 and 2 were also carried out (Table 2) Abstract: N-Linked oligosaccharide processing enzymes are key enzymes in the biosynthesis of N-linked oligosaccharides. These enzymes are a molecular t...

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Enhanced Radical-Scavenging Activity of a Planar Catechin Analogue

Abstract: A catechin analogue in which the geometry was constrained to be planar was synthesized. The planar catechin showed excellent radical-scavenging ability, comparable to that of quercetin, and efficient protection against DNA strand breakage induced by the Fenton reaction.

Cited by 89 publications

References 25 publications

Synthesis and “double-faced” antioxidant activity of polyhydroxylated 4-thiaflavans

Synthesis and “double-faced” antioxidant activity of polyhydroxylated 4-thiaflavans

A Planar Catechin Analogue as a New Type of Synthetic Antioxidant

N-Linked Oligosaccharide Processing Enzymes as Molecular Targets for Drug Discovery

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