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Impact of C18 Epimerization of Indole- and Pyrazole-Fused 18β-Glycyrrhetinic Acid Derivatives on PTP1B and TCPTP
Ledy De-la-Cruz-Martínez1,2,3, Rosendo Martínez-Arellano2,4, Mitzi López-Sánchez2,4
1Doctorado en Ciencias Farmacéuticas, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Unidad Xochimilco, Ciudad de México, 04960, Mexico.
Abstract:
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.
Insights
Synthesizing new analogs of glycyrrhetinic acid (GA) did not enhance protein tyrosine phosphatase 1B (PTP1B) inhibition. Modifications like 18α-H inversion and removing the 11-carbonyl group reduced PTP1B inhibitory activity, suggesting these structural changes are unfavorable for drug development targeting diabetes and obesity.
Area of Science:
- Medicinal Chemistry
- Enzymology
- Molecular Pharmacology
Background:
- Protein tyrosine phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signaling, making it a therapeutic target for diabetes and obesity.
- Existing PTP1B inhibitors derived from 18β-glycyrrhetinic acid (18β-GA) show promise, but more potent compounds are needed.
- 18α-glycyrrhetinic acid (18α-GA) is more potent than 18β-GA, suggesting potential for developing superior inhibitors.
Purpose of the Study:
- To synthesize and evaluate novel 18α-glycyrrhetinic acid (18α-GA) analogs, specifically 18epi-FC114 (3c) and 18epi-FC-122 (5c), based on previously developed PTP1B inhibitors.
- To investigate the impact of structural modifications, including the inversion of the 18-hydroxyl group and the presence/absence of the 11-carbonyl group, on PTP1B inhibitory activity.
- To assess the selectivity of the synthesized compounds against TCPTP and elucidate their mechanism of inhibition.
Main Methods:
- Chemical synthesis of 18epi-FC114 (3c) and 18epi-FC-122 (5c) analogs, with and without the C11 carbonyl group.
- Enzyme inhibition assays to determine the PTP1B inhibitory activity and IC50 values of the synthesized compounds.
- Enzyme kinetics studies to characterize the type of inhibition (uncompetitive) and selectivity assays against TCPTP.
- Molecular docking and dynamics simulations to rationalize the observed structure-activity relationships.
Main Results:
- The synthesized analogs, 18epi-FC114 (3c) and 18epi-FC-122 (5c), exhibited reduced PTP1B inhibitory activity compared to their 18β-GA precursors.
- The inversion of the 18-hydroxyl group to the α-configuration (18α-H) and the absence of the 11-carbonyl group negatively impacted inhibitory potency.
- All tested compounds displayed uncompetitive inhibition of PTP1B and showed no significant inhibition against TCPTP.
- Computational simulations indicated that the 18α-H configuration disrupts crucial interactions with PTP1B, particularly involving the 30-COOH group.
Conclusions:
- Structural modifications involving the 18-hydroxyl group and the 11-carbonyl moiety of glycyrrhetinic acid analogs are detrimental to PTP1B inhibitory activity.
- The synthesized compounds act as uncompetitive inhibitors of PTP1B, offering insights into the enzyme's active site.
- These findings highlight the importance of specific stereochemistry and functional groups for developing effective PTP1B inhibitors for metabolic diseases.
