吲哚和吡唑融合18β-甘草次酸衍生物的C18外聚化对PTP1B和TCPTP抑制活性的影响:合成、体外和硅研究

IF 3.4 4区 医学 Q2 CHEMISTRY, MEDICINAL
ChemMedChem Pub Date : 2025-09-14 DOI:10.1002/cmdc.202500350
Ledy De-la-Cruz-Martínez, Rosendo Martínez-Arellano, Mitzi López-Sánchez, José G Alvarado-Rodríguez, Jesús Martin Torres-Valencia, David Equihua-González, Julio-César Almanza-Pérez, Jaime Pérez-Villanueva, Martín González-Andrade, José C Páez-Franco, Francisco Cortés-Benítez
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引用次数: 0

摘要

蛋白酪氨酸磷酸酶1B (PTP1B)对典型胰岛素和瘦素信号通路的负调控至关重要。这种酶是治疗各种疾病的有效靶点,包括糖尿病和肥胖症。然而,到目前为止,还没有PTP1B抑制剂被批准使用。在早期的研究中,我们开发了两种18β-甘草次酸(18β-GA)的修饰版本FC-114和FC-122,它们比熊果酸(一种众所周知的抑制剂)具有更好的抑制PTP1B的活性。为了开发更强的抑制剂,我们研究了另一种化合物,18α-甘草次酸(18α-GA),它比18β-GA更有效。因此,在本研究中,我们旨在合成类似物18epi-FC114 (3c)和18epi-FC-122 (5c)。这些化合物在C11上有或没有羰基。结果表明,将18β-H转化为18α-H,以及11-羰基的缺失,对PTP1B的抑制活性产生负面影响。然而,合成的化合物对PTP1B表现出非竞争性抑制,对TCPTP酶没有抑制作用。分子对接和动力学模拟表明,18β-H的倒置将30-COOH基团推离,破坏了PTP1B1-400 c末端的相互作用。此外,11-羰基的缺失对化合物的位置不利,限制了同一区域的关键相互作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Impact of C18 Epimerization of Indole- and Pyrazole-Fused 18β-Glycyrrhetinic Acid Derivatives on PTP1B and TCPTP Inhibitory Activity: Synthesis, In Vitro, and In Silico Studies.

Protein tyrosine phosphatase 1B (PTP1B) is crucial for negatively regulating the canonical insulin and leptin signaling pathways. This enzyme is a validated target for treating various disorders, including diabetes and obesity. However, to date, no PTP1B inhibitors have been approved for use. In earlier studies, we developed two modified versions of 18β-glycyrrhetinic acid (18β-GA) called FC-114 and FC-122, which showed better inhibitory PTP1B activity than ursolic acid, a well-known inhibitor. To develop even stronger inhibitors, we looked at another compound, 18α-glycyrrhetinic acid (18α-GA), which is more potent than 18β-GA. Thus, in this study, we aimed to synthesize the analogs 18epi-FC114 (3c) and 18epi-FC-122 (5c). These compounds were prepared with and without the carbonyl group at C11. The results showed that converting 18β-H to 18α-H, as well as the absence of the 11-carbonyl group, negatively impacted the PTP1B inhibitory activity. However, the synthesized compounds exhibited an uncompetitive type of inhibition toward PTP1B and did not inhibit the TCPTP enzyme. Molecular docking and dynamics simulations suggest that the inversion of 18β-H pushes the 30-COOH group away, disrupting interactions at the C-terminal site of PTP1B1-400. Additionally, the absence of the 11-carbonyl group positions the compounds unfavorably, limiting critical interactions in the same region.

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来源期刊
ChemMedChem
ChemMedChem 医学-药学
CiteScore
6.70
自引率
2.90%
发文量
280
审稿时长
1 months
期刊介绍: Quality research. Outstanding publications. With an impact factor of 3.124 (2019), ChemMedChem is a top journal for research at the interface of chemistry, biology and medicine. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies. ChemMedChem publishes primary as well as critical secondary and tertiary information from authors across and for the world. Its mission is to integrate the wide and flourishing field of medicinal and pharmaceutical sciences, ranging from drug design and discovery to drug development and delivery, from molecular modeling to combinatorial chemistry, from target validation to lead generation and ADMET studies. ChemMedChem typically covers topics on small molecules, therapeutic macromolecules, peptides, peptidomimetics, and aptamers, protein-drug conjugates, nucleic acid therapies, and beginning 2017, nanomedicine, particularly 1) targeted nanodelivery, 2) theranostic nanoparticles, and 3) nanodrugs. Contents ChemMedChem publishes an attractive mixture of: Full Papers and Communications Reviews and Minireviews Patent Reviews Highlights and Concepts Book and Multimedia Reviews.
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