JACS Au最新文献

Malaria control and elimination efforts would benefit from the identification and validation of new malaria chemotherapeutics. Recently, a transgenic Plasmodium berghei line was used to perform a series of high-throughput in vitro screens for new antimalarials acting against the parasite sexual stages. The screens identified pyrimidine azepine chemotypes with potent activity. Here, we validate the activity of PyAz90, the most potent pyrimidine azepine chemotype identified, against P. falciparum and P. vivax in the asexual and sexual stages. PyAz90 blocked parasite transmission to the mosquito vector at nanomolar concentrations and inhibited in vitro asexual parasite multiplication with a fast-action profile. Through the generation of P. falciparum PyAz90-resistant parasites and in vitro assays of mitochondrial activity, we identified cytochrome b as a molecular target of PyAz90. This work characterizes a promising chemotype that can be explored for the future development of new antimalarials targeting the Plasmodium cytochrome bc ₁ complex.

The construction of polypeptides was revolutionized by Merrifield's solid-phase synthesis more than half a century ago. Herein, we explore a completely different approach to making peptides. We test an original mechanistic postulate wherein a single peptide made entirely of dehydroalanine (Dha) residues can give rise to regio- and stereodefined peptides by iterative conjugate addition of one- or two-electron nucleophiles. Each nucleophile appends a unique amino acid side chain to the peptide backbone. We show that side chain addition is not random. Side chains are added in one of two ways, in an electrophilicity-gated fashion (most cases) or in a substrate-directed manner, depending on the first nucleophile used in the synthesis. One peptide made in this series, KU04212, a first-in-class polyazole peptide, was found to reduce vascular length density (-17%; p < 0.05) and increase vessel diameter (124%; p < 0.001) in healthy day 6 chick embryos at 24 h post-single dose. It also rescued 75% of the embryos administered a 32-fold lethal dose of ischemia-inducing CoCl₂ after 12 h and 12.5% of the embryos after 24 h. In comparison to three mechanistically distinct vasodilators, e.g., isosorbide mononitrate, amlodipine besylate, and prazosin, only KU04212 showed long-acting effects in vivo, making it an enticing lead for the treatment of ischemic disorders.

The indispensability of a base in Suzuki-Miyaura coupling (SMC) employing organoboronic acids/esters is well recognized, which occasionally induces competitive protodeborylation in organoboron reagents. This phenomenon is particularly pronounced in fluorine-substituted aryl and heteroaryl boron compounds. Here, we show that direct SMC of naphthalene-1,8-diaminato (dan)-substituted aryl boron compounds, Ar-B(dan), characterized by its remarkable stability toward protodeborylation due to their diminished boron-Lewis acidity, occurs utilizing a weak base in conjunction with a palladium/copper cooperative catalyst system. The approach delineated in this study enables the efficient incorporation of various perfluoroaryl- and heteroaryl-B(dan) reagents, while maintaining high functional group tolerance. Furthermore, the inherent inertness of the B(dan) moiety allowed sequential cross-coupling, where other metallic moieties chemoselectively undergo the reaction, thus leading to the concise, protection-free synthesis of oligoarenes. Our results provide a potent approach to a delicate dilemma between a protodeborylation-resistant property and SMC activity intimately linked to boron-Lewis acidity.

The precise theranostic strategy of fluorescence imaging-guided photodynamic therapy (PDT) can effectively mitigate the adverse effect of photosensitizers in normal cells and tissues. However, low tumor enrichment and high diffusivity of photosensitizers significantly compromise the imaging accuracy and PDT effect. In this study, we have developed a nitroreductase (NTR)-activated and self-immobilizing photosensitizer CyNT-F, which showed enhanced enrichment in tumor tissues and facilitated precise and sustained imaging as well as PDT for hypoxia tumors. mPEG-b-PDPA nanomicelles encapsulating photosensitizers underwent dissociation and released CyNT-F in tumor cells. CyNT-F and NTR enzymatically reacted in situ to generate highly reactive quinone methide, subsequently covalently binding to adjacent proteins for fluorescence and PDT activation. CyNT-F exhibited longer intracellular retention (7 days) and effectively inhibited the tumor growth of solid hypoxia tumor. We believe the activatable and self-immobilizing strategy of PDT presents a novel methodology for minimizing the adverse effect and enabling spatiotemporally accurate ablation of diseased cells and tissues.

Eutectogels, a rising category of soft materials, have recently garnered significant attention owing to their remarkable potential in various domains. This innovative class of materials consists of a eutectic solvent immobilized in a three-dimensional network structure. The use of eco-friendly and cost-effective eutectic solvents further emphasizes the appeal of these materials in multiple applications. Eutectogels exhibit key characteristics of most eutectic solvents, including environmental friendliness, facile preparation, low vapor pressure, and good ionic conductivity. Moreover, they can be tailored to display functionalities such as self-healing capability, adhesiveness, and antibacterial properties, which are facilitated by incorporating specific combinations of the eutectic mixture constituents. This perspective article delves into the current landscape and challenges associated with eutectogels, particularly focusing on their potential applications in CO₂ separation, drug delivery systems, battery technologies, biocatalysis, and food packaging. By exploring these diverse realms, we aim to shed light on the transformative capabilities of eutectogels and the opportunities they present to address pressing industrial, academic, and environmental challenges.

[This corrects the article DOI: 10.1021/jacsau.4c00379.].

Competitive sorption enables the emergent phenomenon of enhanced CO₂-based selectivities for gas separation membranes when using microporous polymers with primary amines. However, strong secondary forces in these polymers through hydrogen bonding results in low solvent solubility, precluding standard solution processing approaches to form these polymers into membrane films. Herein, we circumvent these manufacturing constraints while maintaining competitive-sorption enhancements by synthesizing eight representative microporous poly(arylene ether)s (PAEs) with tertiary amines. High-pressure H₂S, CO₂, and CH₄ sorption isotherms were collected for these samples to demonstrate enhanced affinity for acid gases relative to the unfunctional control polymer. Although competitive sorption was observed for all samples, improvements were less pronounced than for primary-amine-functional analogs. For H₂S-based separations, the benefits of competitive sorption offset decreases in selectivity due to plasticization. This detailed study helps to elucidate the role of tertiary amines for acid gas separations in solution-processable microporous PAEs.

DNA-encoded libraries connect the phenotypes of synthetic molecules to a DNA barcode; however, most libraries do not tap into the potential of Darwinian evolution. Herein, we report a DNA-templated synthesis (DTS) architecture to make peptides that are stabilized into α-helical conformations via head-to-tail supramolecular cyclization. Using a pilot library targeting MDM2, we show that repeated screening can amplify a binder from the lowest abundance in the library to a ranking that correlates to binding affinity. The study also highlights the need to design libraries such that the chemistry avoids biases from the heterogeneous yield in DTS.

Ambient electrochemical NO reduction presents a dual solution for sustainable NO reduction and NH₃ synthesis. However, their complex kinetics and energy demands necessitate high-performance electrocatalysts to ensure effective and selective process outcomes. Herein, we report that a two-dimensional Cu-based metal-organic framework (MOF), {[Cu(HL)]·H₂O} _n , (Cu-OUC, H₃L = 5-(2'-carboxylphenoxy)isophthalic acid) acts as a stable electrocatalyst with high efficiency for NO-to-NH₃ conversion. Electrochemical experimental studies showed that in 0.1 M K₂SO₄ solution, the as-prepared Cu-OUC achieved a peak Faradaic efficiency of 96.91% and a notable NH₃ yield as high as 3415.82 μg h^-1 mg^-1. The Zn-NO battery in aqueous solution can produce electricity possessing a power density of 2.04 mW cm^-2 while simultaneously achieving an NH₃ yield of 616.92 μg h^-1 mg^-1. Theoretical calculations revealed that the surface of Cu-OUC effectively facilitates NO activation through a two-way charge transfer mechanism of "electron acceptance and donation", with the *NO formation step being the potential-determining stage. The study pioneers the use of a MOF as an electrocatalyst for ambient NO-to-NH₃ conversion.