Inhibitory activities of anthraquinone and xanthone derivatives against transthyretin amyloidogenesis

Kitakami, R.; Inui, Kishin; Nakagawa, Yusuke; Sawai, Yurika; Katayama, Wakana; Yokoyama, Takeshi; Okada, Takuya; Kanamitsu, Kayoko; Nakagawa, Shinsaku; Toyooka, Naoki; Mizuguchi, Mineyuki

doi:10.1016/j.bmc.2021.116292

Cited by 4 publications

(16 citation statements)

References 69 publications

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“…80−83 The halogenation also increased the amyloid inhibitory activities of xanthone-2-carboxylic acid against amyloidogenesis of V30M-TTR. 66 The effect of halogenation was also investigated for luteolin, which is a flavonoid similar to naringenin. One hydroxyl group in the C-ring of luteolin was replaced with a chlorine.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…This modification was based on the fact that TTR has three halogen binding pockets in the thyroxine-binding channels in the dimer–dimer interface and the finding that the interaction between halogen atoms of small compounds and the halogen binding pockets is important for the stabilization of the tetramer. ,, Cotrina et al suggested that halogenation of TTR ligands may improve their affinity and fibrillogenesis inhibition properties . Such improvement was demonstrated for diflunisal through suboptimal halogen bonding interactions and/or by optimized van der Waals contacts. − The halogenation also increased the amyloid inhibitory activities of xanthone-2-carboxylic acid against amyloidogenesis of V30M-TTR . The effect of halogenation was also investigated for luteolin, which is a flavonoid similar to naringenin.…”

Section: Results and Discussionmentioning

confidence: 99%

“…The supernatants were analyzed by LC−MS/MS as described in a previous study. 66 The transitions (precursor ion > product ion) of 6 and IS (methyltestosterone) were 339.0 > 187.1 (negative) and 303.1 > 109.1 (positive), respectively. Two biological replicates were generated for each sample.…”

Section: (2e)-1-(4-chlorophenyl)-3-[2-hydroxy-46-bis(methoxymethoxy)p...mentioning

confidence: 95%

“…Plasma, eyeball, and brain homogenate were precipitated with four volumes of acetonitrile/IS and centrifuged at 15,000 × g for 10 min at 4 °C. The supernatants were analyzed by LC–MS/MS as described in a previous study . The transitions (precursor ion > product ion) of 6 and IS (methyltestosterone) were 339.0 > 187.1 (negative) and 303.1 > 109.1 (positive), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Much attention has been paid to the use of natural compounds as kinetic stabilizers against ATTR amyloidosis. − The natural compounds include genistein, resveratrol, curcumin, chalcone, glabridin, mangostin, caffeic acid phenethyl ester, (−)-epigallocatechin-3-gallate, and flavonoid. Naringenin (4′,5,7-trihydroxyflavanone) is a racemic flavanone predominantly found in citrus fruits such as grapefruit and orange (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis

et al. 2022

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Misfolding and aggregation of transthyretin are implicated in the fatal systemic disease known as transthyretin amyloidosis. Here, we report the development of a naringenin derivative bearing two chlorine atoms that will be efficacious for preventing aggregation of transthyretin in the eye. The amyloid inhibitory activity of the naringenin derivative was as strong as that of tafamidis, which is the first therapeutic agent targeting transthyretin in the plasma. X-ray crystal structures of the compounds in complex with transthyretin demonstrated that the naringenin derivative with one chlorine bound to the thyroxine-binding site of transthyretin in the forward mode and that the derivative with two chlorines bound to it in the reverse mode. An ex vivo competitive binding assay showed that naringenin derivatives exhibited more potent binding than tafamidis in the plasma. Furthermore, an in vivo pharmacokinetic study demonstrated that the dichlorinated derivative was significantly delivered to the eye.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

Section: (2e)-1-(4-chlorophenyl)-3-[2-hydroxy-46-bis(methoxymethoxy)p...mentioning

confidence: 95%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis

et al. 2022

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Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis

Mizuguchi

Yokoyama

Okada

et al. 2023

Bioorganic & Medicinal Chemistry

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Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma

Mizuguchi,

Nakagawa,

Yokoyama

et al. 2024

J. Med. Chem.

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Transthyretin amyloidosis is a fatal disorder caused by transthyretin amyloid aggregation. Stabilizing the native structure of transthyretin is an effective approach to inhibit amyloid aggregation. To develop kinetic stabilizers of transthyretin, it is crucial to explore compounds that selectively bind to transthyretin in plasma. Our recent findings demonstrated that the uricosuric agent benziodarone selectively binds to transthyretin in plasma. Here, we report the development of benziodarone analogues with enhanced potency for selective binding to transthyretin in plasma compared to benziodarone. These analogues featured substituents of chlorine, bromine, iodine, a methyl group, or a trifluoromethyl group, at the 4-position of the benzofuran ring. X-ray crystal structure analysis revealed that CH••• O hydrogen bonds and a halogen bond are important for the binding of the compounds to the thyroxine-binding sites. The bioavailability of benziodarone analogues with 4-Br, 4-Cl, or 4-CH 3 was comparable to that of tafamidis, a current therapeutic agent for transthyretin amyloidosis.

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Inhibitory activities of anthraquinone and xanthone derivatives against transthyretin amyloidogenesis

Cited by 4 publications

References 69 publications

Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis

Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis

Benziodarone and 6-hydroxybenziodarone are potent and selective inhibitors of transthyretin amyloidogenesis

Development of Benziodarone Analogues with Enhanced Potency for Selective Binding to Transthyretin in Human Plasma

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