Covalent modification of cell membranes has shown promise for tumor imaging and therapy. However, existing membrane labeling techniques face challenges such as slow kinetics and poor selectivity for cancer cells, leading to off-target effects and suboptimal in vivo efficacy. Here, we present an enzyme-triggered self-immobilization labeling strategy, termed E-SIM, which enables rapid and selective labeling of tumor cell membranes with bioorthogonal trans-cycloctene (TCO) handles in vivo. E-SIM utilizes P-TCO, an alkaline phosphatase (ALP) responsive quinone methide (QM) precursor with a TCO group, facilitating the rapid conjugation of high-density TCO handles onto tumor cell membranes via proximity labeling. These TCO groups then react efficiently with tetrazine (Tz)-bearing reporters via a fast bioorthogonal reaction, resulting in significant enrichment of reporters of various sizes and imaging modalities on tumor cell membranes. We demonstrate the efficacy of E-SIM labeling and bioorthogonal reaction for pretargeted multimodality imaging of tumors in vivo. Notably, we achieve selective and efficient installation of Tz-modified Renilla luciferase on tumor cells in vivo, thereby offering highly sensitive bioluminescence signals for detecting and guiding the surgical removal of small human HepG2 liver tumor peritoneal metastases. E-SIM represents a robust tool for precise tumor cell labeling in complex in vivo environments, feasible for pretargeted enrichment of various reporters in tumors for multimodal imaging applications.
Bacterial resistance caused by β-lactamases has been a major threat to public health around the world, seriously weakening the efficacy of β-lactam antibiotics, the most widely used therapeutic agents against infectious diseases. To detect the bacterial resistance to β-lactam antibiotics, particularly specific type of β-lactam antibiotics, in a rapid manner, we report herein a relay-response chemiluminescence assay. This assay mainly consists of two reagents: a β-lactam-caged thiophenol and a thiophenol-sensitive chemiluminescence reporter, both of which are synthetically feasible. The selective hydrolysis of β-lactam by β-lactamase leads to the releasing of free thiophenol, which then triggers the emission of a chemiluminescence signal in a relay manner. Three thiophenol-caged β-lactams, structural analogues of cephalothin, cefotaxime, and meropenem, respectively, have been synthesized. And the application of this assay with these analogues of β-lactam antibiotics allows fast detection of β-lactamase-expressing resistant bacteria and, more impressively, provides detailed information on the resistant scope of bacteria.
Abstract Enzyme‐activatable near‐infrared (NIR) fluorescent probes and photosensitizers (PSs) have emerged as promising tools for molecular imaging and photodynamic therapy (PDT). However, in living organisms selective retention or even enrichment of these reagents after enzymatic activation at or near sites of interest remains a challenging task. Herein, we integrate non‐covalent and covalent retention approaches to introduce a novel “1‐to‐3” multi‐effect strategy—one enzymatic stimulus leads to three types of effects—for the design of an enzyme‐activatable NIR probe or PS. Using this strategy, we have constructed an alkaline phosphatase (ALP)‐activatable NIR fluorogenic probe and a NIR PS, which proved to be selectively activated by ALP to switch on NIR fluorescence or photosensitizing ability, respectively. Additionally, these reagents showed significant enrichment (over 2000‐fold) in ALP‐overexpressed tumor cells compared to the culture medium, accompanied by massive depletion of intracellular thiols, the major antioxidants in cells. The investigation of this ALP‐activatable NIR PS in an in vivo PDT model resulted in complete suppression of HeLa tumors and full recovery of all tested mice. Encouragingly, even a single administration of this NIR PS was sufficient to completely suppress tumors in mice, demonstrating the high potential of this strategy in biomedical applications.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
The expression of Klebsiella pneumoniae carbapenemase (KPC), a type of carbapenem‐hydrolyzing β‐lactamase, in Gram‐negative bacteria has caused significant bacterial resistance to carbapenems, the antibiotic of last resort. Herein, we describe the discovery of 2‐carboxyquinoline boronic acids as inhibitor of KPC. We have identified fluoro‐substituted carboxyquinoline boronic acids 1e as the most potent inhibitor, with an IC50 of 8.3 nM for KPC‐2, while this compound is significantly less efficient at reducing the activity of other β‐lactamases. This compound proved to have low cytotoxicity towards mammalian cells, as well as low hemolysis and antibacterial activity. However, 1e potentiated the efficacy of β‐lactam antibiotics (e.g., meropenem and ceftazidime) against KPC‐2‐expressing resistant Klebsiella pneumonia by up to 256‐fold.
Abstract The emergence of antibiotic resistance, particularly bacterial resistance to β‐lactam antibiotics, the most widely prescribed therapeutic agents for infectious diseases, poses a significant threat to public health worldwide. The discovery of effective therapies against antibiotic‐resistant pathogens has become an urgent need, necessitating innovative approaches to accelerate the identification and development of novel antibacterial agents. On the other hand, the expression of the β‐lactam‐hydrolyzing enzyme (β‐lactamase), the major cause of bacterial resistance to β‐lactam antibiotics, provides a distinctive opportunity to visualize bacterial infection, evaluate the efficacy of existing antibiotics, screen for novel antibacterial agents, and optimize drug dosing regimens in live animals. Herein, a hydrophilicity‐switching, self‐immobilizing, near‐Infrared fluorogenic β‐lactamase probe for the highly sensitive imaging of bacterial infection in live mice is reported. This probe, in addition to a significant increase in fluorescence upon selective hydrolysis by β‐lactamases as conventional β‐lactamase probes, also massively enriches within β‐lactamase‐expressing bacteria (over 1500‐folds compared to the incubation medium), which renders excellent sensitivity in the imaging of bacterial infections in living animals. This agent has proven to enable the assessment of antibiotic therapeutic efficacy and potency of β‐lactamase inhibitors in living animals in a non‐invasive and much more convenient manner.
Michael macht's möglich: Die Titelreaktion, die direkt zu Thiochromanen führt, wird effizient durch ein Thioharnstoffderivat eines China-Alkaloids katalysiert. Das organokatalytische Verfahren umfasst eine neuartige dynamische Racematspaltung durch eine Kaskade aus Michael- und Retro-Michael-Reaktionen.
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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