Asymmetric Synthesis, Structure Determination, and Biologic Evaluation of Isomers of TLAM as PFK1 Inhibitors.

Inhibiting phosphofructokinase-1 (PFK1) is a promising approach for treating lactic acidosis and mitochondrial dysfunction by activating oxidative phosphorylation. Tryptolinamide (TLAM) has been shown as a PFK1 inhibitor, but its complex stereochemistry, with 16 possible isomers complicates further development. We conducted an asymmetric synthesis, determined the absolute configurations, and evaluated the PFK1 inhibitory activity of the TLAM isomers.