Fructose-1,6-bisphosphatase Inhibitors. 2. Design, synthesis, and structure-activity relationship of a series of phosphonic acid containing benzimidazoles that function as 5'-adenosinemonophosphate (AMP) mimics.

Efforts to enhance the inhibitory potency of the initial purine series of fructose-1,6-bisphosphatase (FBPase) inhibitors led to the discovery of a series of benzimidazole analogues with human FBPase IC(50)s < 100 nM. Inhibitor 4.4 emerged as a lead compound based on its potent inhibition of human liver FBPase (IC(50) = 55 nM) and significant glucose lowering in normal fasted rats.

Asymmetric Synthesis of Calyculin C. 2. Synthesis of the C(26)-C(37) Fragment and Model Wittig Couplings.

We report our synthesis of the C(26)-C(37) fragment of serine/threonine protein phosphatase PP1 and PP2A inhibitor calyculin C (1). Outlined in this paper are synthetic approaches to the two components based on disconnection at the C(33)-N(3) amide bond. We report the successful synthesis of the C(33)-C(37) aza-sugar derived from D-lyxose which was coupled onto a C(26)-C(32) aminooxazole originating from L-pyroglutamic acid.

Asymmetric Synthesis of Calyculin C. 1. Synthesis of the C(1)-C(25) Fragment.

We report our synthesis of the C(1)-C(25) fragment of serine/threonine phosphatase PP1 and PP2A inhibitor, calyculin C. Synthetic efforts were directed initially toward the synthesis of a spiroketal core fragment (7), which culminated in completion of the bottom half of the natural product. The synthesis of fragment 7 and subsequent elaboration relied on an allylboration strategy for introduction of chirality.