ACS Medicinal Chemistry Letters最新文献

PD-L1 (programmed death ligand 1), the primary ligand of PD-1 (programmed death 1), is widely expressed across various tumor types. In this study, we developed a novel PET probe, [¹⁸F]AlF-Asp₂-TPP-1, for noninvasive imaging of PD-L1 expression. The probe was synthesized with a radiochemical yield of 13.7%, high radiochemical purity (>95%), and a molar activity exceeding 2.4 GBq/μmol. Stability assays confirmed excellent stability both in vitro and in vivo. Dynamic PET imaging over 90 min revealed rapid tracer accumulation in tumors and other organs within 15 min postinjection. Tumor uptake was 2.48 ± 0.05% ID/g, 1.81 ± 0.20% ID/g, and 0.96 ± 0.09% ID/g at 30, 60, and 90 min, respectively. Collectively, these results suggest that [¹⁸F]AlF-Asp₂-TPP-1 is a promising PET imaging agent for monitoring PD-L1 expression in tumors and may serve as a valuable tool for guiding PD-L1-targeted immunotherapy.

This patent application describes a novel series of 2,4,6-trisubstituted 1,3,5-triazines compounds represented by Formula I. These compounds hold promise for the treatment of cardiovascular disorders, including nonischemic dilated cardiomyopathy and heart failure.

This patent describes novel substituted aryl sulfonamides and sulfuric diamides as potent transglutaminase 2 (TG2) inhibitors. It provides details on the novel substituted aryl sulfonamide and sulfuric diamide compounds, pharmaceutical formulations, and the use of such compounds in the treatment of TG2-related diseases, such as fibrosis, neurodegenerative diseases, autoimmune diseases, and cancers.

Phosphodiesterase 2A (PDE2A) plays a vital role in regulating cyclic nucleotide signaling by hydrolyzing cAMP and cGMP in the central nervous system (CNS). This enzymatic activity is essential for neuronal function, and PDE2A has emerged as a molecular target for neuroimaging in neuropsychiatric disorders and neurodegenerative diseases. In this study, we evaluated the novel ¹¹C-labeled positron emission tomography (PET) radioligand [¹¹C]1 derived from a pyrazolopyrimidine-based PDE2A inhibitor. The radiosynthesis of [¹¹C]1 was accomplished via [¹¹C]methyl iodide-mediated methylation of precursor 9 under mild conditions, yielding [¹¹C]1 with high purity (99%) and high molar activity (154 ± 66 GBq/μmol). In vitro autoradiography demonstrated high radiotracer accumulation in regions with abundant PDE2A expression, including the striatum and substantia nigra. However, dynamic PET imaging in rats showed a relatively uniform distribution throughout the brain and no significant blocking effects. Further optimization in medicinal chemistry is necessary to improve the in vivo performance of the pyrazolopyrimidine-based PDE2A tracer scaffold.

Human fungal infections pose a major global health challenge, underscoring the urgent need for new chemotypes that are effective against multidrug-resistant (MDR) fungal pathogens such as Candida auris. Tambjamines (TAs), previously characterized for their potent antimalarial and antileishmanial activities, were investigated for their antifungal potential. A selected series of TA analogs exhibited excellent in vitro activity against C. albicans and C. auris at low micromolar concentrations. Among them, the antimalarial lead TA, KAR1123 (15), exhibited marked antifungal activity against both strains, with superior inhibition of C. auris, while displaying favorable cytotoxicity, metabolic stability, and pharmacokinetic properties. Structure–activity relationship analyses highlighted key structural elements required for antifungal potency. Collectively, this study represents the first evidence of TA activity against C. auris and establishes a promising foundation for the development of next-generation antifungal agents targeting MDR fungal pathogens.

A new class of benzoxaboroles with a phenylglycine appendage was found to display in vitro blood stage activity against the human malaria parasite Plasmodium falciparum (Pf). Structure–activity relationship studies of the starting hit compound 3 resulted in compounds active against PfNF54 drug-sensitive and PfK1 drug-resistant strains with an in vitro antiplasmodium IC₅₀ < 0.4 μM, selectivity over mammalian cell-lines (selectivity index > 47) and high aqueous solubility (160 to >200 μM). Selected compounds showed good in vitro metabolic stability when incubated with human, rat, and mouse liver microsomes and showed no cross-resistance against barcoded mutant lines. Two frontrunner compounds, 6 and 7, were dosed orally at 50 mg·kg^–1 using a standard quadrupole dosing regimen in a P. berghei mouse infection model and showed encouraging in vivo efficacy. This work identifies a promising new class of phenylglycine-based benzoxaboroles, which warrants further medicinal chemistry optimization.

Nuclear receptor related 1 (Nurr1) is a neuroprotective transcription factor emerging as a promising target in Parkinson’s disease and multiple sclerosis. It can act in three oligomeric forms as monomer, homodimer, and heterodimer on different DNA response elements. We hypothesized that dual Nurr1 and RXR activation might enable the selective modulation of Nurr1 in its heterodimeric form. A search for dual ligands revealed valerenic acid and a synthetic mimetic as Nurr1 and RXR activators. Biochemical and cellular characterization demonstrated that dual agonism destabilized the Nurr1 homodimer but left the heterodimer intact, which translated into selective activation of the heterodimer response element in cells. In neuronal cells, a dual Nurr1/RXR agonist enhanced expression of only a subset of Nurr1 agonist induced genes, providing initial proof-of-concept for the dimer-directed selective Nurr1 modulation approach.

Hypertension represents a severe cardiovascular pathology linked to the increase in reactive oxygen species that impair blood vessel function. Herein, we report on the synthesis of hybrid compounds designed to release H₂S and incorporate natural or semisynthetic scaffolds capable of activating the Nrf2 pathway. The molecular hybrids enable a multitarget approach concurrently inducing vasorelaxation upon H₂S release and mitigating oxidative stress through Nrf2-dependent antioxidant responses via the upregulation of cytoprotective proteins, including HO-1. The itaconate derivative 8b displayed an optimal H₂S release in both amperometric and cellular assays. In human aortic smooth muscle cells, compound 8b counteracted ROS production and cytotoxicity in H₂O₂-injured cells and led to the activation of potassium channels with consequent cell hyperpolarization and vasorelaxation, which was also observed in isolated rat aortic rings. Overall, our findings indicate that simultaneous Nrf2 activation and H₂S release hold significant potential as a new therapeutic strategy for the treatment of hypertension.

The DNA repair enzyme O⁶-Methylguanine DNA Methyltransferase (MGMT) is a major contributor in conferring resistance to alkylating agents such as temozolomide (TMZ) in cancers. The use of MGMT inhibitors can suppress resistance and enhance the efficacy of TMZ. However, current inhibitors are nonselective for cancer cells, and as a result, MGMT is also inhibited in healthy cells leading to severe side effects. Here, we report the development of a photoactivatable MGMT inhibitor, whereby irradiation is required for MGMT inhibition and subsequent enhancement of the TMZ sensitivity in T98G cells. This strategy is promising for tissue-specific therapy, whereby TMZ efficacy can only be enhanced in the cancerous region and not healthy tissue, controlled spatially by light.