作者: Richa, Kikoleho ; Ritse, Vimha ; Rudithongru, Lemzila ; Nakro, Vevosa ; Jamir, Latonglila ; Sinha, Upasana Bora ; Ao, Imkongyanger ; Ao, Ketiyala ; Namsa, Nima D. ; Lotha, Tsenbeni N. ; Pankaj, Pranay Punj

Background:Type 2 Diabetes Mellitus (T2DM) represents a significant and pressing worldwide health concern, necessitating the quest for enhanced antidiabetic pharmaceuticals. Guanidine derivatives, notably metformin and buformin, have emerged as pivotal therapeutic agents for T2DM management.Aims:The present study introduces an efficient one-pot synthesis method for the production of symmetrical guanidine compounds and subsequently, their evaluation as potential T2DM agents.Methods:This synthesis involves the reaction of isothiocyanates with secondary amines, employing an environmentally friendly and recyclable reagent, tetrabutylphosphonium tribromide (TBPTB). In order to understand the mechanics of ligand-protein interaction, ADME/Toxicity, and drug-likeliness aspects, in silico studies were incorporated.Results:An efficient and easy method for synthesis of guanidine compounds has been devised. Comprehensive assessment of the biological activity of the synthesized guanidine compounds, specifically in the context of T2DM, has been rigorously conducted.Conclusion:Computational analyses have unveiled their substantial potential as promising antidiabetic agents. Results highlight the relevance of these compounds in the ongoing pursuit of novel therapeutic solutions for T2DM.

2025-01-01·Journal of Chromatography B

Non-targeted screening of illegal added hypoglycemic drugs and their derivatives in functional foods using characteristic fragment ions scanning based on liquid chromatography-high-resolution mass spectrometry

Article

作者: Liu, Yajie ; Feng, Xuesong ; Wang, Xiujuan ; Du, Rongzhu ; Zhang, Feng ; Feng, Feng

Functional foods that are illegally adulterated with chemical hypoglycemic drugs or their derivatives pose serious risks to human health. However, the detection of these compounds is a challenge due to the unknown nature of their structures, particularly as many of these compounds are newly synthesized and lack standardized references. In this study, we developed a non-targeted screening strategy for detecting illegally added hypoglycemic drugs and their derivatives in oral solution and hard capsule functional foods. This strategy utilizes a self-established characteristic fragment ions mass spectrum database based on ultrahigh-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry. Nine characteristic fragment ions were identified by analyzing the mass spectrometric fragmentation patterns of hypoglycemic drugs. Meanwhile, the precursor and fragment ions of 38 known hypoglycemic drugs were collected and incorporated into the mass database. The detection limits of hypoglycemic drugs in oral solution and hard capsule samples were 0.01-10 μg/L and 0.01-50 μg/kg, respectively. Applying the non-targeted method to 20 batches of suspicious samples, we found that 3 batches of samples contained illegal added drugs. Furthermore, we identified a previously unrecorded hypoglycemic drug not present in the mass database. These results indicate that the developed strategy is a powerful tool for the rapid and highly sensitive identification of both known and unknown hypoglycemic drugs, as well as their derivatives in functional foods.

2024-11-01·Journal of Biological Chemistry

Comprehensive characterization of the OCT1 phenylalanine-244-alanine substitution reveals highly substrate-dependent effects on transporter function

Article

作者: Schröder, Sophie ; Brockmöller, Jürgen ; Gebauer, Lukas ; Jensen, Ole ; Wittern, Carla Isabel

Organic cation transporters (OCTs) can transport structurally highly diverse substrates. The molecular basis of this extensive polyspecificity has been further elucidated by cryo-EM. Apparently, in addition to negatively charged amino acids, aromatic residues may contribute to substrate binding and substrate selectivity. In this study, we provide a comprehensive characterization of phenylalanine 244 in OCT1 function. We analyzed the uptake of 144 OCT1 substrates for the phenylalanine 244 to alanine substitution compared to WTOCT1. This substitution had highly substrate-specific effects ranging from transport reduced to 10% of WT activity up to 8-fold increased transport rates. Four percent of substrates showed strongly increased uptake (>200% of WT) whereas 39% showed strongly reduced transport (<50% of WT). Particularly with larger, more hydrophobic, and more aromatic substrates, the Phe244Ala substitution resulted in higher transport rates and lower inhibition of the transporter. In contrast, substrates with a lower molecular weight and less aromatic rings showed generally decreased uptake rates. A comparison of our data to available transport kinetic data demonstrates that generally, high-affinity low-capacity substrates show increased uptake by the Phe244Ala substitution, whereas low-affinity high-capacity substrates are characterized by reduced transport rates. Altogether, our study provides the first comprehensive characterization of the functional role of an aromatic amino acid within the substrate translocation pathway of OCT1. The pleiotropic function further highlights that phenylalanine 244 interacts in a highly specific manner with OCT1 substrates and inhibitors.

100 项与盐酸丁福明相关的药物交易

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