ChemMedChem最新文献

Boron Neutron Capture Therapy (BNCT) leverages the nuclear reaction between boron-10 and thermal neutrons to selectively destroy cancer cells while minimizing damage to surrounding healthy tissues. This therapy has found use in treating glioblastoma, which as a brain cancer, is difficult to treat using conventional radiotherapy, surgery, and chemotherapy due to location and the risk of brain damage. However, to work, the cells must contain 10B. 4-Borono-l-phenylalanine (l-BPA) is the most frequently used boron delivery agent in this therapy. Surprisingly, despite its seemingly simple structure, there is no consensus approach to making it-the synthesis of l-BPA has been approached through multiple routes, reflecting the challenges in producing high-purity, isotopically enriched material. When a new site is looking to make this essential material, it can be challenging to determine the best route for the situation as there is no critical analysis comparing and discussing the relative merits of the approaches. Herein, we comprehensively and critically examine and compare the reported methods, from both the academic and patent literature, used to synthesize l-BPA. The review also highlights the limitations of each method regarding scalability, cost-effectiveness, and safety, especially considering the high cost of isotopically enriched 10B.

Galectin-3 (Gal-3), a β-galactoside-binding lectin, is implicated in diverse cellular functions ranging from immune response modulation to tissue homeostasis. Notably, increased Gal-3 expression has been linked to the progression of numerous diseases, including cancer, fibrosis, and cardiovascular disorders, underscoring its potential as a therapeutic target. Small molecule inhibitors have been discovered and are valuable tools to study such diseases. We report here the discovery of novel, galactose-based, small molecule inhibitors such as compound 12 which are orally bioavailable and show efficacy in a mouse model of acute liver injury and fibrosis (CCl₄ model). The use of structure-based drug design (docking of a virtual library of amides based on acid 2) was key in the process towards potent, nanomolar inhibitors.

A new series of isoniazid-dihydropyrimidinone molecular hybrids (8a-8n) were designed, synthesized and structurally characterized using different spectroscopic techniques viz., Fourier transform infrared spectroscopy, nuclear magnetic resonance (NMR), and high-resolution mass spectrometry followed by their antitubercular evaluation including their precursors (4a-4n), and a standard antitubercular drug (isoniazid; INH). The molecular hybrids particularly 8g (minimum inhibitory concentration (MIC) = 6.25 μg mL^-1), 8h (MIC = 1.56 μg mL^-1), 8k (MIC = 0.78 μg mL^-1), 8l (MIC = 6.25 μg mL^-1), and 8n (MIC = 0.39 μg mL^-1) demonstrated the most potent inhibitory activity against wild-type M. tuberculosis mc²6230, disclosing 8n as the most potent compound in the series. However, the potent compounds lost their activity against three INH-resistant M. tuberculosis strains mutated in katG. The more efficient compounds (8h, 8k, and 8n) were subsequently evaluated for their cytotoxicity against the THP-1 human monocytic cell line. Furthermore, the stability studies of the most potent compound carried out using ¹H NMR, UV-visible, and liquid chromatography-mass spectrometry revealed their structural integrity. Finally, in silico molecular docking simulations were conducted to explore the binding orientations of the potent compounds in the active site of the target protein InhA while ADME/T (absorption, distribution, metabolism, excretion, and toxicity) and global reactivity parameters were explored to determine their drug-likeness and stability profiles, respectively.

Lanosterol is the crucial intermediate in ergosterol biosynthesis in fungi. A number of derivatives of natural or synthetic origin of these sterols are portrayed in this review. For the synthetic derivatives, strategies of their syntheses are presented. Biological activities of lanosterol and ergosterol derivatives include antimicrobial, especially antifungal action, anticancer and antiviral effects but also anti-inflammatory and anti-allergic potential. The most promising seems to be the anticancer potential of peroxides, epoxides, and keto- derivatives of both sterols.

Antibody-drug conjugates (ADCs) have emerged as a powerful form of targeted therapy that can deliver drugs with a high level of selectivity towards a specific cell type, reducing off-target effects and increasing the therapeutic window compared to small molecule therapeutics. However, creating ADCs that are stable, homogeneous, and with controlled drug-to-antibody ratio (DAR) remains a significant challenge. Whilst a myriad of methods have been reported to generate ADCs with a DAR of 2, 4, and 8, strategies to generate DAR 1 constructs are seldom reported despite the advantages of low drug loading to tune ADC properties or to allow access to antibody-antibody and antibody-protein constructs. This concept article highlights the diversity of methods that have been employed to access single-payload ADCs and explores the outlook for the field.

Shown on the cover is the hyperpolarization chemistry of α-ketoglutarate using parahydrogen in reversible exchange. Alpha-ketoglutarate is one example of the broad class of α-ketocarboxylates hyperpolarized in this work. These α-ketocarboxylates represent important biomarkers for the study of in vivo metabolic processes. The NMR and MRI sensitivity of these hyperpolarized biomarkers is enhanced by up to 30000-fold. More details can be found in article 10.1002/cmdc.202400378 by Stephen J. McBride, Thomas Theis, and co-workers.

The cover art features an iridium complex with distinct cyclometalated ligands that enhance both bioimaging and therapeutic properties. The illustration also highlights the therapeutic function, where the iridium complex, upon light irradiation, induces apoptosis or cellular damage, representing its targeted cancer-fighting capabilities. The review article presents the current advancements and future potential of cyclometalated iridium (III) complexes as a phototheranostic agent. The finding demonstrates that cyclometalated iridium (III) complexes hold significant promise for both bioimaging and therapeutic purposes, showcasing potent anticancer activity that addresses the limitations of conventional cancer therapies by enabling more effective targeted delivery. More details can be found in article 10.1002/cmdc.202400649 by Priyankar Paira and co-workers.

Stroke is the second highest cause of death and leading cause of disability with high economic burden worldwide. The incidence of stroke is increasing faster and more prevalent for the global population over age 65. Ischemic stroke (IS) has a higher incidence than hemorrhagic stroke, accounting over 80 % of the total incidence of stroke. The rate of ischemic stroke is increasing in all age groups and both sexes. In present era, hypertension, high blood pressure and modern lifestyle are considered as the causes of the disease. The treatment options for stroke is still limited, mainly thrombolytic and thrombectomy therapy are available options. In the past decade, a number of therapeutic agents have been studied for the acute ischemic stroke to protect the brain from ischemic injury. Several study methods focus to improve neurons functions around the ischemic core and protect from the shock. Many signalling pathways including NF-kB, NrF, Nrf2-Keap1, PI3K/AKT, JAK/STAT signalling pathways are strongly associated for the indication. Controlling the signalling pathways by small molecules potentially improve the neuronal functions. In this article, we review the recent advancement of the drug discovery, controlling the signalling pathways by small molecules, and kinase inhibitors in ischemic stroke.

The Gram-negative, pathogenic bacteria Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) have been identified as a particular threat due to rising multidrug resistance, and antibiotics with novel mechanisms of action are needed. Bacterial bioenergetics is a promising but underdeveloped drug target since the complexes of oxidative phosphorylation are critical to cell survival in these organisms. Building from our previous work using quinoline derivatives to inhibit the ATP synthase of PA, we report a new set of 14 quinoline derivatives that demonstrates potent inhibition of the AB ATP synthase, with the best inhibitor having an IC50 of 230 ng/mL in vitro, expands the quinoline structure-activity relationship against the PA enzyme, and establishes molecular strategies for achieving selectivity between PA and AB. Furthermore, several compounds demonstrated potent antibacterial activity against multidrug resistant strains of AB and PA indicating ATP synthase as a promising new area for broad spectrum antibiotic development in AB.

The severe adverse effects associated with imbalanced cyclooxygenase-2 (COX-2) inhibition continue to pose significant challenges in the development of contemporary anti-inflammatory drugs. In recent years, the approach to COX-2 inhibitor drug development has shifted from a focus on highly selective inhibition of COX-2 to a strategy that emphasizes more moderate selectivity. The amino acid sequence and structural similarities between inducible COX-2 and constitutive cyclooxygenase-1 (COX-1) isoforms present both substantial opportunities and challenges for the design of next generation of balanced COX-2 inhibitors. As part of our ongoing research into the discovering novel and safer COX-2 inhibitors, we reported herein a highly potent and balanced COX-2 inhibitor 21 d (IC₅₀ value=1.35 μM, selectivity profile (IC₅₀ (COX-1)/IC₅₀ (COX-2)=22.34)). In vivo assays demonstrated that 21 d significantly alleviated histological damage and provided robust protection against dextran sulfate sodium (DSS)-induced acute colitis.