1. Transthyretin amyloidosis

Amyloidogenesis, the process through which extracellular cross-β-sheet amyloid fibrils accumulate, is associated with at least 30 different proteins; it is a hallmark of Alzheimer’s disease, Parkinson’s disease, and other late-onset neurodegenerative diseases.

Transthyretin (TTR) aggregation is the cause of several inherited and sporadic amyloid disorders, including familial transthyretin amyloid cardiomyopathy (ATTR-CM) and wild-type ATTR-CM. Under physiological conditions, TTR exists as a 54 kDa homotetrameric protein secreted into the blood by the liver and into the cerebrospinal fluid by the choroid plexus that primarily functions in transporting thyroxine (T₄) and the holo retinol-binding protein. TTR amyloidogenesis is caused by rate-limiting tetramer dissociation followed by partial monomer denaturation that renders TTR aggregation competent.

                                                                                                                                                                         (Neurology 2012 79 785)

Interestingly, although TTR is known to be one of the human amyloidogenic proteins representative of pathological conditions, TTR has also been implicated in the neuroprotection of Alzheimer’s disease. Evidence for the latter emerged from the following results: (1) TTR is one of the major Ab-binding proteins in human CSF, suppressing Ab aggregation and is involved in brain Ab efflux and peripheral clearance through proteolytic functions; (2) overexpression of WT-TTR in an APP23 transgenic mouse model showed improved cognitive functions; (3) TTR levels are reduced both in the CSF and the blood of Alzheimer’s disease patients, compared with age-matched controls.

Research Area

  - The development of non-covalent TTR aggregation inhibitors that occupy two T₄ binding sites with a high affinity 

  - The development of covalent TTR aggregation inhibitors that chemoselectively react with the ε-amino group of Lys15 on the                 periphery of the two T₄ binding pockets.

- The development of small molecules with unique photophysical properties that could potentially serve as and fluorescent TTR           sensors.

2. Synthesis of Biologically important Heteroaromatics 

Bioactive nitrogen-containing heterocycles and fluoro-substituted molecules are ubiquitous in various fields, such as medicinal chemistry, agrochemistry, and material chemistry. Substantial effort has been made to develop modular synthetic methodologies for preparing members of this family. Recently, our group have been developed to access oxazoline/ thiazoline cores, fluoro(alkyl)-substituted molecules, trifluoro- and pentafluoro-substituted thiazoles. 

                   Scheme 1. Synthesis of Thio(seleno)cyano-difluoroalkylation of Alkenes Using Visible-Light Photocatalysis 

                                            Scheme 2. Thiazole synthesis using hypervalent iodine reagent

Research Area

  - The development of efficient methods for the synthesis of heterocycles using Cu-catalyzed reaction and hypervalent iodine 

  - The development of efficient methods for the synthesis of fluoro-substituted molecules using Cu-catalyzed reaction and                        photochemistry