Pharmaceutical chemistry

Leucine dehydrogenase (LeuDH, EC 1.4.1.9) can reversibly catalyze the oxidative deamination of l-leucine and some other specific α-amino acids to form the corresponding α-ketoacids. This reaction has great significance in the field of food additives and the pharmaceutical industry. The LeuDH from Exiguobacterium sibiricum ( Es LeuDH) has high catalytic efficiency but limited thermal stability, hindering its widespread industrial application. In this study, a mutant N5F/I12L/A352Y of Es LeuDH (referred to as M2) was developed with enhanced thermal stability and catalytic activity through rational modification...

To fully explore the potential of 18 F-labeled l-fluoroalanine for imaging cancer and other chronic diseases, a simple and mild radiosynthesis method has been established to produce optically pure l-3-[18 F]fluoroalanine (l-[18 F]FAla), using a serine-derivatized, five-membered-ring sulfamidate as the radiofluorination precursor. A deuterated analogue, l-3-[18 F]fluoroalanine-d3 (l-[18 F]FAla-d3 ), was also prepared to improve metabolic stability. Both l-[18 F]FAla and l-[18 F]FAla-d3 were rapidly taken up by 9L/lacZ, MIA PaCa-2, and U87MG cells and were shown to be substrates for the alanine-serine-cysteine (ASC) amino acid transporter...

Type II kinase inhibitors bind in the "DFG-out" kinase conformation and are generally considered to be more potent and selective than type I inhibitors, which target a DFG-in conformation. Nine type II inhibitors are currently clinically approved, with more undergoing clinical development. Resistance-conferring secondary mutations emerged with the first series of type II inhibitors, most commonly at residues within the kinase activation loop and at the "gatekeeper" position. Recently, new inhibitors have been developed to overcome such mutations; however, mutations activating other pathways (and/or other targets) have subsequently emerged on occasion...

Palladium-catalyzed cross-couplings of aryl chlorides usually call for bulky, electron-rich ligands such as phosphines or heterocyclic carbenes. We have now found that similarly powerful cross-coupling catalysts are obtained by the reaction of palladium salts with alkynyllithium reagents. The species initially formed in this process was characterized as a dilithium tetraalkinyl palladate complex. It catalyzes the coupling of aryl chlorides with the lithium salts of various terminal alkynes to give alkynyl arenes...

Breast cancer is the second most frequent cancer among women. Out of various subtypes, triple-negative breast cancers (TNBCs) account for 15% of breast cancers and exhibit more aggressive characteristics as well as a worse prognosis due to their proclivity for metastatic progression and limited therapeutic strategies. It has been demonstrated that AMP-activated protein kinase (AMPK) has context-specific protumorigenic implications in breast cancer cells. A set of glucosyltriazole amphiphiles, consisting of acetylated (9a-h) and unmodified sugar hydroxyl groups (10a-h), were synthesized and subjected to in vitro biological evaluation...

The synthetic medicinal chemist plays a vital role in drug discovery. Today there are AI tools to guide next syntheses, but many are "Black Boxes" (BB). One learns little more than the prediction made. There are now also AI methods emphasizing visibility and "explainability" (thus explainable AI or XAI) that could help when "compositional data" are used, but they often still start from seemingly arbitrary learned weights and lack familiar probabilistic measures based on observation and counting from the outset...

Vinyl sulfones are crucial building blocks in synthetic chemistry and core structural units of pharmaceutically active molecules, thus extensive investigations have been conducted on the construction of these skeletons. In contrast to the classical synthetic approaches, the radical sulfonylation of alkynes for producing vinyl sulfones has garnered considerable interest because of its mild conditions and high efficiency. Radical sulfonation of alkynes typically begins with the sulfonyl radical attacking the alkynes, followed by further functionalization...

Breast cancer remains a global health challenge, and innovative strategies are required to target estrogen receptor α (ERα), a key player in its development. This study investigates the potential of campesterol, a natural phytosterol, as an ERα inhibitor for breast cancer. Our approach integrates in silico , in vitro , and ex vivo experiments to assess the therapeutic potential of campesterol. In silico analyses highlight campesterol as a promising ERα ligand with favorable binding affinities and dynamic properties...

While large-scale artificial intelligence (AI) models for protein structure prediction and design are advancing rapidly, the translation of deep learning models for practical macromolecular drug development remains limited. This investigation aims to bridge this gap by combining cutting-edge methodologies to create a novel peptide-based PROTAC drug development paradigm. Using ProteinMPNN and RFdiffusion, we identified binding peptides for androgen receptor (AR) and Von Hippel-Lindau (VHL), followed by computational modeling with Alphafold2-multimer and ZDOCK to predict spatial interrelationships...

Aragon et al. [Acta Cryst. (2024), C80, 179-189], by reporting the discussion and the final conclusions of a round table held during a symposium at the National Center for CryoEM Access and Training, well describe all the advances that have been made for the application of 3D ED/MicroED to pharmaceutical and macromolecular nanocrystals and propose possible future scenarios.

BACKGROUND: Guigan longmu decoction (GGLM), a traditional Chinese medicine compound, has demonstrated efficacy in treating rapid arrhythmia clinically. Nevertheless, its mechanism of action remains elusive. This study aims to elucidate the molecular mechanism underlying the efficacy of GGLM in treating arrhythmia utilizing non-targeted metabolomics, widely-targeted metabolomics, and network pharmacology, subsequently validated through animal experiments. METHODS: Initially, network pharmacology analysis and widely-targeted metabolomics were performed on GGLM...

AIMS: We aim to explore GATA6 modulation in allergic rhinitis (AR). BACKGROUND: Circular RNAs (circRNAs) and microRNAs (miRNAs) are involved in inflammatory responses; GATA6 is also known to regulate multiple inflammatory pathways. However, the mechanism of regulation of AR between them is unclear. OBJECTIVE: We expect that this study will provide new treatment options for AR from a GATA6 perspective. METHODS: In vitro, AR models were employed to examine the efficacy of our study, where we utilized monoclonal anti-2,4,6-dinitrophenyl immunoglobulin (Ig) E/human serum albumin (DNP-IgE/HSA) to induce rat basophilic leukemia cells (RBL-2H3 cells)...

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Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), which remains a significant global health challenge. The emergence of multidrug-resistant (MDR) Mtb strains imposes the development of new therapeutic strategies. This study focuses on the identification and evaluation of potential inhibitors against Mtb H37Ra through a comprehensive screening of an in-house chemolibrary. Subsequently, a promising pyrimidine derivative (LQM495) was identified as promising and then further investigated by experimental and in silico approaches...

The marine metabolite diazonamide A exerts low nanomolar cytotoxicity against a range of tumor cell lines; however, its highly complex molecular architecture undermines the therapeutic potential of the natural product. We demonstrate that truncation of heteroaromatic macrocycle in natural diazonamide A, combined with the replacement of the challenging-to-synthesize tetracyclic hemiaminal subunit by oxindole moiety leads to considerably less complex analogues with improved drug-like properties and nanomolar antiproliferative potency...

A novel strategy for the difunctionalization of electron-deficient alkenes with aryl sulfonium salts to access remote sulfur-containing oxindole derivatives by using in situ-formed copper(I)-based complexes as a photoredox catalyst is presented. This method enables the generation of the C(sp3 )-centered radicals through site selective cleavage of the C-S bond of aryl sulfonium salts under mild conditions. Moreover, the oxidation reactions of desired products provide a new strategy for the preparation of sulfoxide or sulfone-containing compounds...

Addressing the global fossil energy crisis necessitates the efficient utilization of sustainable energy sources. Hydrogen, a green fuel, can be generated using sunlight, water, and a photocatalyst. Employing sensitizers holds promise for enhancing photocatalyst performance, enabling high rates of hydrogen evolution through increased visible light absorption. However, sifting through millions of diverse molecules to identify suitable dyes for specific photocatalysts poses a significant challenge. In this study, we integrate genetic algorithm and geometry-frequency-noncovalent extended tight binding methods to efficiently screen 2...

The C(sp3 )-N bond is ubiquitous in natural products, pharmaceuticals, biologically active molecules and functional materials. Consequently, the development of practical and efficient methods for C(sp3 )-N bond formation has attracted more and more attention. Compared to the conventional ionic pathway-based thermal methods, photochemical processes that proceed through radical mechanisms by merging photoredox and transition-metal catalyses have emerged as powerful and alternative tools for C(sp3 )-N bond formation...

The new ligand L2Ad , obtained by conjugating the bifunctional species bis(3,5-dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of new Cu complexes 1 - 5 . Their structures were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and by combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modeling. The structure of complex 3 was determined by single-crystal X-ray diffraction analysis...

Intervertebral disc degeneration (IDD) is a common musculoskeletal system disease, which is one of the most important causes of low back pain. Despite the high prevalence of IDD, current treatments are limited to relieving symptoms, and there are no effective therapeutic agents that can block or reverse the progression of IDD. Oxidative stress, the result of an imbalance between the production of reactive oxygen species (ROS) and clearance by the antioxidant defense system, plays an important role in the progression of IDD...