Studi Padatan dengan Differential Scanning Calorimetry dan Scanning Electron Microscope pada Mikrosfer Pautan Silang Alginat yang Mengandung Metformin HCl

Tujuan dari penelitian ini adalah mempelajari interaksi fisika antara alginat dan metformin HCl dalam bentuk mikrosfer. Interaksi fisika diamati dengan menggunakan differential scanning calorimetry (DSC) dan scanning electron microscope (SEM). Mikrosfer dengan efisiensi penjeratan optimum ditentukan jenis interaksinya dengan DSC yang didukung dengan analisis morfologi mikrosfer yang dihasilkan oleh SEM. Termogram DSC menunjukkan interaksi fisika metformin HCl-matriks alginat yang ditunjukkan dengan perubahan profil kurva endotermik pada suhu 228-230°C dan 265-35°C. Hasil SEM mikrosfer menunjukan bahwa metformin berada dalam bentuk kristal sedangkan alginat hasil pautan silang dalam bentuk amorf. Dapat disimpulkan bahwa interaksi fisika yang terjadi adalah ikatan hidrogen yang kuat antara metformin HCl dengan alginat yang berefek pada meningkatnya efisiensi penjeratan

Ruthenium-catalysed C‒H amidation for the late-stage synthesis of PROTACs

PROteolysis TArgeting Chimeras (PROTACs) are a powerful modality in drug discovery, offering the potential to address outstanding medical challenges. However, the synthetic feasibility of PROTACs, and the empiric and complex nature of their structure-activity relationships continue to present formidable limitations. As such, modular and reliable approaches to streamline the synthesis of these compounds are highly desirable. Here, we describe a robust ruthenium-catalysed late-stage C‒H amidation strategy, to provide modular access to both fully elaborated PROTACs and drug conjugates. Using readily available dioxazolone reagents, a broad range of inherently present functional groups can guide the C–H amidation on complex bioactive molecules. High selectivity and functional group tolerance enable the late-stage installation of linkers bearing orthogonal functional handles for downstream elaboration. Finally, the single-step synthesis of PROTAC and biotin conjugates is demonstrated, showcasing the potential of this methodology to provide efficient and sustainable access to advanced therapeutics and chemical biology tools

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3‑3 Protein–Protein Interaction

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein–protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators

Designing Selective Drug-like Molecular Glues for the Glucocorticoid Receptor/14-3‑3 Protein–Protein Interaction

The ubiquitously expressed glucocorticoid receptor (GR) is a nuclear receptor that controls a broad range of biological processes and is activated by steroidal glucocorticoids such as hydrocortisone or dexamethasone. Glucocorticoids are used to treat a wide variety of conditions, from inflammation to cancer but suffer from a range of side effects that motivate the search for safer GR modulators. GR is also regulated outside the steroid-binding site through protein–protein interactions (PPIs) with 14-3-3 adapter proteins. Manipulation of these PPIs will provide insights into noncanonical GR signaling as well as a new level of control over GR activity. We report the first molecular glues that selectively stabilize the 14-3-3/GR PPI using the related nuclear receptor estrogen receptor α (ERα) as a selectivity target to drive design. These 14-3-3/GR PPI stabilizers can be used to dissect noncanonical GR signaling and enable the development of novel atypical GR modulators