Organofluorine inhibitors of amyloid fibrillogenesis

Biochemistry
Marianna TörökBéla Török

Abstract

The design and application of an effective, new class of organofluorine inhibitors of amyloid fibrillogenesis are described. Based on experimental evidence a core structure containing indol-3-yl, trifluoromethyl, hydroxyl, and carboxylic acid ester functions has been designed. Several substituted derivatives of this core structure have been synthesized, using various indole derivatives. While all inhibitor candidates have shown considerable effect (20-70% inhibition) in structure-activity relationship studies (inhibitor/Abeta = 10 ratio), several compounds have demonstrated excellent activity (93-96% inhibition). Using concentration dependence studies, the activity of the most active molecules have been quantified. These inhibitors practically completely block the fibril formation of Abeta(1)(-)(40), as shown by maximum inhibition values (IC(max) = 98-100%). The median inhibitor concentration values (IC(50) = 0.23-0.53 mol(inhibitor)/mol(A)(beta)) demonstrate favorable stoichiometry for the inhibition. The respective elimination of the functional groups from the core structure has resulted in a partial or complete loss of activity, indicating the significant role of each group. Experiments with these derivatives suggest the par...Continue Reading

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Citations

Jan 26, 2013·Biochemistry·Béla TörökMarianna Török
Mar 1, 2011·Bioorganic & Medicinal Chemistry Letters·Abha SoodMarianna Török
Jun 1, 2007·Journal of Fluorine Chemistry·Mohammed AbidBéla Török
Jul 17, 2010·Proteins·Takako TakedaDmitri K Klimov
Dec 28, 2010·Journal of Molecular Biology·Timothy M RyanGeoffrey J Howlett
Dec 15, 2010·European Journal of Medicinal Chemistry·Francesco CampagnaGerardo Palazzo
Nov 3, 2009·Bioorganic & Medicinal Chemistry Letters·Abha SoodMarianna Török
Feb 3, 2015·Organic & Biomolecular Chemistry·M KamlarJ Veselý
Dec 30, 2014·Bioorganic & Medicinal Chemistry Letters·Seema BagMarianna Török
Jul 20, 2018·Chemical Communications : Chem Comm·Ling-Yu BaoZhi-Guo Gu
Aug 4, 2018·Organic & Biomolecular Chemistry·Kajal MalChhanda Mukhopadhyay
Aug 19, 2007·Amyloid : the International Journal of Experimental and Clinical Investigation : the Official Journal of the International Society of Amyloidosis·Harry LeVine
Jun 29, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Rosa PurgatorioMarco Catto
Apr 28, 2014·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Joana A LoureiroSandra Rocha
Apr 29, 2020·International Journal of Molecular Sciences·Meghna DaburMaria Carmo Pereira
Jan 28, 2020·Current Organic Synthesis·Anne KokelBéla Török
Jan 16, 2009·Journal of Medicinal Chemistry·Aleksandra RudnitskayaKimberly Stieglitz
Jun 8, 2021·International Journal of Biological Macromolecules·Hossein AshrafianRizwan Hassan Khan
Jan 8, 2013·ACS Medicinal Chemistry Letters·Kai LiuShijun Zhang
Nov 26, 2010·Chemical Reviews·Maria J ClimentSara Iborra

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