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

Mizuguchi, Mineyuki; Yokoyama, Takeshi; Okada, Takuya; Nakagawa, Yusuke; Fujii, Kenta; Nabeshima, Yuko; Toyooka, Naoki

doi:10.1016/j.bmc.2023.117370

Cited by 5 publications

(15 citation statements)

References 68 publications

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“…Figure shows the percent TTR occupancy by 4 , 5 , 6 , 7 , and 8 in human plasma . The percent TTR occupancy by 4 , 5 , 6 , 7 , and 8 was higher than that of 1 and 3 across the concentration range of 2.5 to 20 μM (Figures and ).…”

Section: Resultsmentioning

confidence: 90%

“…Compound 4 adopted two binding modes in the thyroxine-binding site of V30M-TTR (Figures and ). In both binding modes, the hydroxy diiodophenyl group of 4 overlapped with that of 3 (Figure A,B) . In addition, two iodine atoms of 4 were located at the same position as the iodine atoms of thyroxine in complex with wild-type TTR (Figure C,D) .…”

Section: Resultsmentioning

confidence: 97%

“…Since human plasma contains numerous proteins, it is important to develop kinetic stabilizers that selectively bind to TTR in human plasma. Nonselective binding to plasma components other than TTR compromises the efficacy of kinetic stabilizers. ,− We have previously demonstrated that 3 is a potent and selective kinetic stabilizer of TTR . In this study, we report the development of benziodarone analogues that are more potent in selective binding to plasma TTR than 3 .…”

Section: Resultsmentioning

confidence: 99%

“…These benziodarone analogues clearly inhibited the amyloid aggregation of V30M-TTR (Figure A). The amyloid aggregation of V30M-TTR was also analyzed at various compound concentrations ranging from 0 to 50 μM (Figure B) . The values of the half-maximal inhibitory concentration (IC 50 ) of the benziodarone analogues are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

“… In addition, we have recently demonstrated that benziodarone ( 3 ) and its possible metabolite 6-hydroxybenziodarone are potent for selective binding to TTR in human plasma (Figure ). The compound 3 with a hydroxy diiodophenyl ring was more potent in binding to TTR in plasma than 2 with a hydroxy dibromophenyl ring . Therefore, we considered that 3 was a promising lead compound for the development of kinetic stabilizers with high potency for selective binding to TTR in plasma.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Visible‐Light‐Induced Radical Sulfonylative‐Cyclization Cascade of 1,6‐Enynol Derivatives with Sulfinic Acids: A Sustainable Approach for the Synthesis of 2,3‐Disubstituted Benzoheteroles

Haritha Kumari,

Jagadesh Kumar,

Sharadha

et al. 2024

ChemSusChem

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Benzoheteroles are promising structural scaffolds in the realm of medicinal chemistry, but sustainable synthesis of 2,3‐difunctionalized benzoheterole derivatives is still in high demand. Indeed, we have conceptually rationalized the intrinsic reactivity of propargylic‐enyne systems for the flexible construction of 2,3‐disubstituted benzoheteroles through radical sulfonylative‐cyclization cascade under organophotoredox catalysis. We hereby report an efficient visible‐light‐induced sulfonyl radical‐triggered cyclization of 1,6‐enynols with sulfinic acids under the dual catalytic influence of 4CzIPN and NiBr2.DME, which led to the formation of 2,3‐disubstituted benzoheteroles in good to high yields. Additionally, the Rose Bengal (RB)‐catalyzed radical sulfonylative‐cycloannulation of acetyl‐derived 1,6‐enynols with sulfinic acids under blue LED irradiation provided access to 3‐(E‐styryl)‐derived benzofurans and benzothiophenes in moderate to good yields. The scope and limitations of the present strategies were successfully established using different classes of 1,6‐enynols and sulfinic acids bearing various sensitive functional groups, yielding the desired products in a highly stereoselective fashion. Plausible mechanistic pathways were also proposed based on the current experimental and control experiments.

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Thyroxine metabolite-derived 3-iodothyronamine (T1AM) and synthetic analogs as efficient suppressors of transthyretin amyloidosis

Kim,

Ko,

et al. 2023

Computational and Structural Biotechnology Journal

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

Cited by 5 publications

References 68 publications

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

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

Visible‐Light‐Induced Radical Sulfonylative‐Cyclization Cascade of 1,6‐Enynol Derivatives with Sulfinic Acids: A Sustainable Approach for the Synthesis of 2,3‐Disubstituted Benzoheteroles

Thyroxine metabolite-derived 3-iodothyronamine (T1AM) and synthetic analogs as efficient suppressors of transthyretin amyloidosis

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