Asymmetric\nSynthesis, Structure Determination, and\nBiologic Evaluation of Isomers of TLAM as PFK1 Inhibitors

Inhibiting phosphofructokinase-1 (PFK1) is a promising\napproach\nfor treating lactic acidosis and mitochondrial dysfunction by activating\noxidative phosphorylation. Tryptolinamide (TLAM) has been shown as\na PFK1 inhibitor, but its complex stereochemistry, with 16 possible\nisomers complicates further development. We conducted an asymmetric\nsynthesis, determined the absolute configurations, and evaluated the\nPFK1 inhibitory activity of the TLAM isomers. Our structure–activity\nrelationship (SAR) study of TLAM isomers revealed that both carboline\nand norbornene configurations influence PFK1 inhibitory activity.\nAmong isomers <b>1a</b>–<b>1d</b>, compound <b>1c</b> was the most potent PFK1 inhibitor. Our elucidation of\nthe SAR information on PFK1 inhibitors provides valuable insights\nfor effective optimization.