Synthesis of 5(S)-Methyl-L-Proline containing Peptidomimetic Compounds and their In-Vitro Evaluation for Dipeptidyl Peptidase-4 Inhibition

Background: Type 2 diabetes mellitus (T2DM), which is the epidemic of the 21st century, has affected millions of people worldwide. Traditional methods available for the treatment are associated with various side effects. Among the newer therapies, DPP-4 (Dipeptidyl peptidase-4) inhibition has been a promising therapy for the past decade with the scope of further development, especially in peptidomimetics. Objective: 5(S)-methyl-L-proline containing peptidomimetic compounds were designed in the previous work. The designed compounds were synthesized and characterized by spectral methods, such as mass spectrometry, 1H NMR, and 13C NMR (Nuclear magnetic resonance) spectroscopy. The purity of the final compounds was determined by high-performance liquid chromatography (HPLC). The synthesized compounds were in vitro evaluated for their DPP-4 inhibitory activity. Method: Compounds were peptide in nature and were synthesized using the conventional synthesis approach, where peptide synthesis was done using an acid-amine coupling reagent. They were evaluated through fluorimetric enzyme-based assay using a DPP-4 inhibitor screening kit. Moreover, the CLARIOstar microplate reader instrument was used to measure fluorescence. Results: 5(S)-methyl-L-proline containing 13 compounds were synthesized. All of them were characterized for structural integrity using spectral methods. They had HPLC purity of more than 95% and were evaluated for DPP-4 inhibition. Compounds 001, 007, 010, 011, 014, and 017 were found to have good inhibition than others. These compounds were further evaluated at different concentrations to develop a linear correlation coefficient (R2). Conclusion: Six compounds were found to have good DPP-4 inhibition, hence it further opens the possibility of developing DPP-4 inhibitor-containing 5(S)-methyl-L-proline.

GNSS-IR Measurements of Inter Annual Sea Level Variations in Thule, Greenland from 2008–2019

Studies of global sea level often exclude Tide Gauges (TGs) in glaciated regions due to vertical land movement. Recent studies show that geodetic GNSS stations can be used to estimate sea level by taking advantage of the reflections from the ocean surface using GNSS Interferometric Reflectometry (GNSS-IR). This method has the immediate benefit that one can directly correct for bedrock movements as measured by the GNSS station. Here we test whether GNSS-IR can be used for measurements of inter annual sea level variations in Thule, Greenland, which is affected by sea ice and icebergs during much of the year. We do this by comparing annual average sea level variations using the two methods from 2008–2019. Comparing the individual sea level measurements over short timescales we find a root mean square deviation (RMSD) of 13 cm, which is similar to other studies using spectral methods. The RMSD for the annual average sea level variations between TG and GNSS-IR is large (18 mm) compared to the estimated uncertainties concerning the measurements. We expect that this is in part due to the TG not being datum controlled. We find sea level trends from GNSS-IR and TG of −4 and −7 mm/year, respectively. The negative trend can be partly explained by a gravimetric decrease in sea level as a result of ice mass changes. We model the gravimetric sea level from 2008–2017 and find a trend of −3 mm/year.

IN SILICO MODELLING, SYNTHESIS, AND ANTI-DIABETIC EVALUATION OF BENZOTHIAZOLE SUBSTITUTED OXADIAZOLE DERIVATIVES

Objective: The study contemplates in silico modeling, synthesis and in-vitro anti-diabetic evaluation of benzothiazole substituted oxadiazole derivatives. [{5-[(1, 3-benzothiazol-2-ylsulfanyl) methyl]-1, 3, 4-oxadiazol-2-yl} sulfanyl) methyl] derivatives were synthesized by a conventional method. Methods: All the newly synthesized derivatives were characterized by determining their melting point, retention factor from thin-layer chromatography, and spectral methods (Infrared, 1H NMR spectroscopy, 13C NMR spectroscopy, Mass spectroscopy) and evaluated for their anti-diabetic activity. Results: [{5-[(1, 3-benzothiazol-2-ylsulfanyl) methyl]-1, 3, 4-oxadiazol-2-yl} sulfanyl) methyl] derivatives have been made and characterized using physical and spectral methods. The in-vitro anti-diabetic screening study revealed that BZT1 and BZT4 exhibited high inhibition against glucose uptake assay and alpha-amylase enzyme. But only the derivative BZT4 showed inhibition against alpha-glucosidase enzyme. Conclusion: Various benzothiazole substituted oxadiazole derivatives were synthesized, characterized by spectral studies. The anti-diabetic studies revealed that the synthesized derivatives have significant anti-diabetic properties and further structure-activity relationship studies may develop more potent and less toxic molecules.

Clustering Vertex-Weighted Graphs by Spectral Methods

Spectral techniques are often used to partition the set of vertices of a graph, or to form clusters. They are based on the Laplacian matrix. These techniques allow easily to integrate weights on the edges. In this work, we introduce a p-Laplacian, or a generalized Laplacian matrix with potential, which also allows us to take into account weights on the vertices. These vertex weights are independent of the edge weights. In this way, we can cluster with the importance of vertices, assigning more weight to some vertices than to others, not considering only the number of vertices. We also provide some bounds, similar to those of Chegeer, for the value of the minimal cut cost with weights at the vertices, as a function of the first non-zero eigenvalue of the p-Laplacian (an analog of the Fiedler eigenvalue).