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. Our structure-activity relationship (SAR) study of TLAM isomers revealed that both carboline and norbornene configurations influence PFK1 inhibitory activity. Among isomers 1a-1d, compound 1c was the most potent PFK1 inhibitor. Our elucidation of the SAR information on PFK1 inhibitors provides valuable insights for effective optimization.