Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors

Asensio González; Josefina Quirante; Joan Nieto; Maria Rosário Almeida; Maria Joao Saraiva; Antoni Planas; Gemma Arsequell; Gregorio Valencia

doi:10.1016/j.bmcl.2009.03.004

Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors

Asensio González, Josefina Quirante, Joan Nieto, Maria Rosário Almeida, Maria Joao Saraiva, Antoni Planas, Gemma Arsequell, Gregorio Valencia

IQS School of Engineering

Research output: Indexed journal article › Article › peer-review

47 Citations (Scopus)

Abstract

The isatin core structure was found to be a novel chemical scaffold in transthyretin (TTR) fibrillogenesis inhibitor design. Among the series of isatin analogues prepared and tested, the nitro compound 1,3-dihydro-3-[(4-nitrophenyl)imino]-2H-indol-2-one (2r) is as potent as triiodophenol, which is one of the most active known TTR inhibitors. The E/Z stereochemistry of these molecules in solution, elucidated by ¹H NMR, does not influence their biological activity. The compounds do not bind to the native tetrameric TTR suggesting that their inhibitory action is independent of the protein binding and stabilization.

Original language	English
Pages (from-to)	5270-5273
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	17
DOIs	https://doi.org/10.1016/j.bmcl.2009.03.004
Publication status	Published - 1 Sept 2009

Keywords

Amyloidosis
Inhibitors
Isatins
Transthyretin

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title = "Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors",

abstract = "The isatin core structure was found to be a novel chemical scaffold in transthyretin (TTR) fibrillogenesis inhibitor design. Among the series of isatin analogues prepared and tested, the nitro compound 1,3-dihydro-3-[(4-nitrophenyl)imino]-2H-indol-2-one (2r) is as potent as triiodophenol, which is one of the most active known TTR inhibitors. The E/Z stereochemistry of these molecules in solution, elucidated by 1H NMR, does not influence their biological activity. The compounds do not bind to the native tetrameric TTR suggesting that their inhibitory action is independent of the protein binding and stabilization.",

keywords = "Amyloidosis, Inhibitors, Isatins, Transthyretin",

author = "Asensio Gonz{\'a}lez and Josefina Quirante and Joan Nieto and Almeida, {Maria Ros{\'a}rio} and Saraiva, {Maria Joao} and Antoni Planas and Gemma Arsequell and Gregorio Valencia",

note = "Funding Information: This work was financially supported by grants to projects POCI/SAU-MMO/57321/2004 from FCT-Funda{\c c}{\~a}o para a Ci{\^e}ncia e Tecnologia (Portugal) and CTQ2006-02390/BQU and BIO2007-67904-C02-02 from Ministerio de Ciencia y Tecnologia (Spain). ",

year = "2009",

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doi = "10.1016/j.bmcl.2009.03.004",

language = "English",

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journal = "Bioorganic and Medicinal Chemistry Letters",

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AU - González, Asensio

AU - Quirante, Josefina

AU - Nieto, Joan

AU - Almeida, Maria Rosário

AU - Saraiva, Maria Joao

AU - Planas, Antoni

AU - Arsequell, Gemma

AU - Valencia, Gregorio

N1 - Funding Information: This work was financially supported by grants to projects POCI/SAU-MMO/57321/2004 from FCT-Fundação para a Ciência e Tecnologia (Portugal) and CTQ2006-02390/BQU and BIO2007-67904-C02-02 from Ministerio de Ciencia y Tecnologia (Spain).

PY - 2009/9/1

Y1 - 2009/9/1

N2 - The isatin core structure was found to be a novel chemical scaffold in transthyretin (TTR) fibrillogenesis inhibitor design. Among the series of isatin analogues prepared and tested, the nitro compound 1,3-dihydro-3-[(4-nitrophenyl)imino]-2H-indol-2-one (2r) is as potent as triiodophenol, which is one of the most active known TTR inhibitors. The E/Z stereochemistry of these molecules in solution, elucidated by 1H NMR, does not influence their biological activity. The compounds do not bind to the native tetrameric TTR suggesting that their inhibitory action is independent of the protein binding and stabilization.

AB - The isatin core structure was found to be a novel chemical scaffold in transthyretin (TTR) fibrillogenesis inhibitor design. Among the series of isatin analogues prepared and tested, the nitro compound 1,3-dihydro-3-[(4-nitrophenyl)imino]-2H-indol-2-one (2r) is as potent as triiodophenol, which is one of the most active known TTR inhibitors. The E/Z stereochemistry of these molecules in solution, elucidated by 1H NMR, does not influence their biological activity. The compounds do not bind to the native tetrameric TTR suggesting that their inhibitory action is independent of the protein binding and stabilization.

KW - Amyloidosis

KW - Inhibitors

KW - Isatins

KW - Transthyretin

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AN - SCOPUS:68549085257

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JO - Bioorganic and Medicinal Chemistry Letters

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IS - 17

ER -

Isatin derivatives, a novel class of transthyretin fibrillogenesis inhibitors

Abstract

Keywords

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