Figure - available from: Frontiers in Pharmacology
This content is subject to copyright.
Source publication
This work aimed to discover protein tyrosine phosphatase 1B (PTP1B) inhibitors from a small molecule library of natural products (NPs) derived from selected Mexican medicinal plants and fungi to find new hits for developing antidiabetic drugs. The products showing similar IC50 values to ursolic acid (UA) (positive control, IC50 = 26.5) were conside...
Similar publications
Background
Protein tyrosine phosphatase 1B (PTP1B) is a protein tyrosine phosphatase and modulates platelet‐derived growth factor (PDGF)/platelet‐derived growth factor receptor (PDGFR) signaling in vascular smooth muscle cells (VSMCs) via endocytosis. However, the related molecular pathways that participated in the interaction of endo‐lysosome and...
Citations
Diazophosphonates function as indispensable synthetic intermediates within the domain of organic chemistry, serving as precursors for a diverse range of molecules, with potential applications as bioactive compounds. α-Diazomethylphosphonates showcase expansive reactivity and elevated levels of enantioselectivity in asymmetric transformations, especially in conjunction with suitable catalyst systems. This review compiles the latest advancements in diazophosphonate chemistry from 2016 to 2024, highlighting their reactivity and transformative potential in organic synthesis. Diazophosphonates, regarded as revolutionary compounds, exhibit unique attributes as carbene precursors, driving diverse chemical reactions such as [3+2] cycloaddition, asymmetric [3+2] cycloaddition, asymmetric [3+3] cycloaddition, and asymmetric substitution reactions. Their adaptability in functional group conversions underscores their pivotal role in various synthetic methodologies. The review highlights the growing interest in diazophosphonate reactions among synthetic chemists, fostering novel synthetic strategies and expanding their application horizons. The multifaceted utility of diazophosphonates as reagents, synthetic intermediates, precursors, and catalysts underscores their significance in modern organic chemistry and pharmaceutical applications, prompting further exploration into this dynamic field.
1 Introduction
2 [3+2] Cycloaddition Reactions
3 Asymmetric [3+2] Cycloaddition Reactions
4 Asymmetric [3+3] Cycloaddition Reactions
5 Asymmetric Substitution Reactions
6 Diazophosphonates as Carbene Precursors
7 Diazophosphonates in the Chemistry of Fluorinated Compounds
8 Other Reactions
9 Future Directions
10 Conclusion
Protein tyrosine phosphatase 1B (PTP1B) is a promising drug target for treating type 2 diabetes (T2DM) and obesity. As a result, developing new therapies that target PTP1B is an attractive strategy for treating these diseases. Herein, we detail the synthesis of 15 lithocholic acid (LA) derivatives, each containing different benzylaminomethyl groups attached to the C3 position of the steroid skeleton. The derivatives were assessed against two forms of PTP1B enzyme (hPTP1B 1−400 and hPTP1B 1−285), and the most potent compounds were then tested against T-cell protein tyrosine phosphatase (TCPTP) to determine their selectivity. The results showed that compounds 6m and 6n were more potent than the reference compounds (ursolic acid, chlorogenic acid, suramin, and TCS401). Additionally, both compounds exhibited greater potency over hPTP1B 1−400. Furthermore, enzyme kinetic studies on hPTP1B 1−400 revealed that these two lithocholic acid derivatives have an uncompetitive inhibition against hPTP1B 1−400 with K i values of 2.5 and 3.4 μM, respectively. Interestingly, these compounds were around 75-fold more selective for PTP1B over TCPTP. Finally, docking studies and molecular dynamics simulations (MDS) were conducted to determine how these compounds interact with PTP1B. The docking studies revealed hydrophobic and H-bond interactions with amino acid residues in the unstructured region. MDS showed that these interactions persisted throughout the 200 ns simulation, indicating the crucial role of the unstructured zone in the biological activity and inhibition of PTP1B.
