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

Ryo Kakehi; Hiroki Kobayashi; Haruna Mashiyama; Tatsuo Yajima; Hiroo Koyama; Takashi K Ito; Minoru Yoshida; Yasuo Nagaoka; Takaaki Sumiyoshi

doi:10.1021/acsmedchemlett.4c00436

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

ACS Med Chem Lett. 2024 Dec 4;16(1):59-63. doi: 10.1021/acsmedchemlett.4c00436. eCollection 2025 Jan 9.

Authors

Ryo Kakehi¹, Hiroki Kobayashi^{2

3}, Haruna Mashiyama³, Tatsuo Yajima⁴, Hiroo Koyama⁵, Takashi K Ito⁶, Minoru Yoshida^{3

6

7

8}, Yasuo Nagaoka¹, Takaaki Sumiyoshi¹

Affiliations

¹ Department of Life Science and Biotechnology, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan.
² Laboratory of Oncology, School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan.
³ Seed Compounds Exploratory Unit for Drug Discovery Platform, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁴ Department of Chemistry and Materials Engineering, Faculty of Chemistry, Materials and Bioengineering, Kansai University, 3-3-35 Yamate-cho, Suita, Osaka 564-8680, Japan.
⁵ Drug Discovery Platforms Cooperation Division, Drug Discovery Chemistry Platform Unit, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁶ Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
⁷ Office of University Professors, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
⁸ Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.

PMID: 39811129
PMCID: PMC11726387 (available on 2026-01-09)
DOI: 10.1021/acsmedchemlett.4c00436

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 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.