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

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-12-04 eCollection Date: 2025-01-09 DOI:10.1021/acsmedchemlett.4c00436

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

引用次数: 0

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.

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TLAM作为PFK1抑制剂异构体的不对称合成、结构测定和生物学评价。

通过激活氧化磷酸化，抑制磷酸果糖激酶-1 （PFK1）是治疗乳酸酸中毒和线粒体功能障碍的一种很有前途的方法。Tryptolinamide （TLAM）已被证明是一种PFK1抑制剂，但其复杂的立体化学，有16种可能的异构体进一步发展。我们进行了不对称合成，确定了绝对构型，并评估了TLAM异构体的PFK1抑制活性。我们对TLAM异构体的构效关系（SAR）研究表明，碳碱和降木片烯构型都会影响PFK1抑制活性。在同分异构体1a-1d中，化合物1c是最有效的PFK1抑制剂。我们对PFK1抑制剂SAR信息的阐明为有效优化提供了有价值的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.