Design and synthesis of N–acetylglucosamine derived 5a-carbasugar analogues as glycosidase inhibitors

An efficient synthesis of new six-membered carbasugars in both L-form and D-form starting from N–acetylglucosamine is described. The key synthetic steps involved regioselective protection and deprotection, Ferrier carbocyclization, Peterson olefination, hydroboration and stereoselective epoxidation followed by regioselective epoxide ring opening reactions. These six-membered carbasugars showed moderate glycosidase inhibitory activity and one of the compounds was found selective towards β-galactosidase inhibitory activity.     

Development of a validated liquid chromatographic method for the determination of related substances and assay of tenofovir disoproxil fumarate

The present study describes the development and validation of a selective liquid chromatographic (LC) method for the analysis of tenofovir disoproxil fumarate (TDF) and its related substances. The gradient method uses a base deactivated C18 column (Hypersil BDS column; 25 cm×4.6 mm I.D.) maintained at a temperature of 30°C. The mobile phases consist of acetonitrile, tetrabutylammonium/phosphate buffer pH 6.0 and water: (A; 2:20:78 v/v/v) and (B; 65:20:15 v/v/v). The flow rate is 1.0 mL/min and UV detection is performed at 260 nm. Good separation of TDF and 21 impurities was achieved. A system suitability test (SST) to check the quality of separation is also specified. The developed method was further validated with respect to robustness, precision, sensitivity and linearity. The method is proved to be robust, precise, sensitive and linear between 0.1 μg/mL and 0.15 mg/mL. The limit of detection and limit of quantification are 0.03 and 0.1 μg/mL, respectively. The method was successfully applied to the quantification of related substances and assay of commercial TDF samples (bulk substances and tablets).     

Stereoselective total synthesis of the cytotoxic lactone (−)-spicigerolide

A highly stereoselective synthesis of the naturally occurring lactone (−)-spicigerolide has been achieved utilizing OsO₄-catalyzed dihydroxylation, CBS, Lindlar’s reductions, Still-Gennari, and Grignard reactions as the key reaction steps.     

Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy

Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.