Tuning transthyretin amyloidosis inhibition properties of iododiflunisal by combinatorial engineering of the nonsalicylic ring substitutions.
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.
Unit of Glycoconjugate Chemistry, I.Q.A.C.-C.S.I.C. , 08034 Barcelona, Spain.
Maria
M
Vilaró
Joan
J
Nieto
Juan Ramón
JR
La Parra
Maria Rosário
MR
Almeida
Alfredo
A
Ballesteros
Antoni
A
Planas
Gemma
G
Arsequell
Gregorio
G
Valencia
D028227:Amyloid Neuropathies, Familial / Q000517:prevention & control*; D020650:Combinatorial Chemistry Techniques; D004061:Diflunisal / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D013329:Structure-Activity Relationship
C504815:iododiflunisal; D004061:Diflunisal
5-aryl salicylic acid core libraries; Barluenga’s reagent; TTR amyloidosis inhibitors; aqueous Suzuki-Miyaura reaction; iododiflunisal analogues library; polymer-supported iodonium reagent; solution-phase parallel synthesis; transthyretinkinetic stabilizers