Tuning transthyretin amyloidosis inhibition properties of iododiflunisal by combinatorial engineering of the nonsalicylic ring substitutions.

Abstract

Two series of iododiflunisal and diflunisal analogues have been obtained by using a two step sequential reaction solution-phase parallel synthesis. The synthesis combined an aqueous Suzuki-Miyaura cross-coupling and a mild electrophilic aromatic iodination step using a new polymer-supported iodonium version of Barluenga's reagent. From a selected set of 77 noniodinated and 77 iodinated diflunisal analogues, a subset of good transthyretin amyloid inhibitors has been obtained with improved turbidimetry inhibition constants, high binding affinity to transthyretin, and good selectivity for TTR compared to other thyroxine binding proteins.

• Authors: Maria Vilaró, Joan Nieto, Juan Ramón La Parra, Maria Rosário Almeida, Alfredo Ballesteros, Antoni Planas, Gemma Arsequell, Gregorio Valencia
• Journal: ACS combinatorial science (ACS Comb Sci) Vol. 17 Issue 1 Pg. 32-8 (Jan 12 2015) ISSN: 2156-8944 [Electronic] United States
• PMID: 25394203 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• iododiflunisal
• Diflunisal

Topics

• Amyloid Neuropathies, Familial (prevention & control)
• Combinatorial Chemistry Techniques
• Diflunisal (analogs & derivatives, therapeutic use)
• Humans
• Structure-Activity Relationship