Development of new halogenated compounds as transthyretin misfolding inhibitors: role of the halogen bond

Thyroid hormones are well known halogen bond (XB) donors as shown by short I···O contacts that underlie the selective binding of hormone thyroxine (T4) to transthyretin (TTR).[1] This protein is composed of four subunits, which are organized into a homotetrameric quaternary structure with two dimer-dimer interfaces.Dissociation of the native tetramer and subsequent aggregation to form insoluble amyloid fibrils are involved in several TTR amyloidosis (ATTR) diseases. Over the past decade, it was observed that T4 and other small molecules could inhibit the tetramer dissociation, and therefore be efficacious against ATTR diseases.[1] However, currently, these diseases still lack an effective therapy. On this basis, we describe herein the development of new atropisomeric iodinated 4,4'-bipyridines (IBPYs)[2] as TTR misfolding inhibitors. In particular, a docking study was performed in order to inspect interactions and binding modes of the IBPYs into the TTR. The (M)-2-iodo-4,4'-bipyridyl substructure has been identified as suitable for developing the new TTR stabilizers (Figure b). Interestingly, in this case, a XB was observed between the 2-iodine of IBPY and the side chain of Ser117' with distance and angle values in accord with what is defined as XB biomolecular contacts (penetration of the van der Waals atomic spheres -2.8%, angles: C-I···O = 149.34° and I···O-C = 111.85°).[3] References [1] Johnson, S. M., Wiseman, R. L., Sekijima, Y., Green, N. S., Adamski-Weiner, S. L., Kelly, J. W., Acc. Chem. Res. 2005, 38, 911-921. [2] (a) Mamane, V., Aubert, E., Peluso, P., Cossu, S., J. Org. Chem. 2013, 78, 7683-7689; (b) Mamane, V., Peluso, P., Aubert, E., Cossu, S., Pale, P., J. Org. Chem. 2016, 81, 4576-4587. [3] Ho, P. S., Top. Curr. Chem. 2015, 358, 241-276. Acknowledgement: This work has been supported by Università Ca' Foscari di Venezia, Italy (DSMN, ADIR funds). V. M. thanks the International Center Frontier Research in Chemistry (icFRC) and the Laboratory of Excellence for Complex System Chemistry (LabEx CSC).