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 <b>1a</b>-<b>1d</b>, compound <b>1c</b> was the most potent PFK1 inhibitor. Our elucidation of the SAR information on PFK1 inhibitors provides valuable insights for effective optimization.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2024-12-04
DOI
https://doi.org/10.1021/acsmedchemlett.4c00436
Citations
1
Primary Topic
Enzyme function and inhibition
Type
article
Field-Weighted Citation Impact
0.23

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article

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

Hiroki Kobayashi, Takaaki Sumiyoshi, Minoru Yoshida, Tatsuo Yajima et al.
1 citations
ACS Medicinal Chemistry Letters
Enzyme function and inhibition
0.23
article

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

Hiroki Kobayashi, Takaaki Sumiyoshi, Minoru Yoshida, Tatsuo Yajima, Hiroo Koyama, Tetsufumi Ito, Yasuo Nagaoka, Ryo Kakehi, Haruna Mashiyama
article en
1 citations

Abstract

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 <b>1a</b>-<b>1d</b>, compound <b>1c</b> was the most potent PFK1 inhibitor. Our elucidation of the SAR information on PFK1 inhibitors provides valuable insights for effective optimization.

ACS Medicinal Chemistry LettersVol. 16(1)
Tokyo University of Pharmacy and Life Sciences (JP), RIKEN Center for Sustainable Resource Science (JP), Kansai University (JP), The University of Tokyo (JP)
Takeda Science Foundation, Novartis Foundation, Japan Agency for Medical Research and Development, Kansai University, NOVARTIS Foundation (Japan) for the Promotion of Science, Japan Society for the Promotion of Science, Japan Science and Technology Agency
Zero hunger
Openalex Percentile: Top 40%
Enzyme function and inhibition
0.23
DOIOpen Access PDFOpenAlex
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Asymmetric Synthesis, Structure Determination, and Biologic Evaluation of Isomers of TLAM as PFK1 Inhibitors — Hiroki Kobayashi, Takaaki Sumiyoshi, et al. · ACS Medicinal Chemistry Letters (2024) | TGRS Research Map | TGRS