The synthesis of a number pyrrolo-annelated tetrathiafulvalenes, including the parent bis(pyrrolo[3,4-d])tetrathiafulvalene (7) is decribed. Starting from readily available 4,5-bis(bromomethyl)-1, 3-dithiole-2-thione (14) and sodium tosylamide, the parent 7 and the asymmetric monopyrrolo tetrathiafulvalenes 23a,b were prepared in good yields via a nonclassical and simple pyrrole synthesis. Furthermore, a series of asymmetrical N-alkylated monopyrrolo/monodihydropyrrolotetrathiafulvalenes was prepared starting from primary amines and 14. A detailed study of the fundamental redox behavior of this class of heterocycles is reported. NMR spectroscopy, cyclic voltammetry, and PM3 MO calculations revealed that the pyrrolo-annelated tetrathiafulvalenes have highly extended pi-surfaces. The X-ray crystallographic analyses of the monopyrrolo tetrathiafulvalenes 22b and 24b, together with preliminary formation of a charge-transfer complex between the parent donor 7 and TCNQ, are also reported.

The design of small and high-affinity lectin inhibitors remains a major challenge because the natural ligand binding sites of lectin are often shallow and have polar character. Herein we report that derivatizing galactose with un-natural structural elements that form multiple non-natural lectin-ligand interactions (orthogonal multipolar fluorine-amide, phenyl-arginine, sulfur-π, and halogen bond) can provide inhibitors with extraordinary affinity (low nanomolar) for the model lectin, galectin-3, which is more than five orders of magnitude higher than the parent galactose; moreover, is selective over other galectins.

Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene expression in liver myofibroblasts and displayed antifibrotic activity in CCl4-induced liver fibrosis and bleomycin-induced lung fibrosis mouse models. On the basis of the overall pharmacokinetic, pharmacodynamic, and safety profile, GB1211 was selected as the clinical candidate and is currently in phase IIa clinical trials as a potential therapy for liver cirrhosis and cancer.