Nitroreductase-Activated Probes for Monitoring Hypoxia.

Hypoxia, a hallmark of solid tumors, complicates cancer treatment by reducing the efficacy of radiotherapy and chemotherapy. To optimize strategies for hypoxia detection and targeted cancer therapy, this work explores the development of hypoxia-responsive fluorescent probes. In this study, we compared various nitroaromatic groups and both elimination-based and cyclization-based self-immolative designs to study nitroreductase (NTR) activation.

Discovery of WEE1 Kinase Inhibitors with Potent Activity against Patient-Derived, Metastatic Colorectal Cancer Organoids.

A library of potent WEE1 kinase inhibitors was synthesized based on the discontinued frontrunner clinical candidate AZD1775 (), many of which were more selective for WEE1 over an undesirable off-target of , the kinase PLK1. When tested against patient-derived organoids (PDOs) grown from -mutated colorectal cancer (CRC) peritoneal metastases, (IC value of 62 nM) exhibited stronger efficacy than (IC value of 120 nM) and the best-in-class clinical candidate ZN-c3 (IC value of 127 nM). Against primary CRC PDOs with -WT, significantly enhanced DNA damage, replication stress and apoptosis compared to , as well as demonstrated high selectivity over patient-matched normal healthy colon PDOs, highlighting a potential therapeutic window for cancer treatment.

Phenotypic-Based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium tuberculosis.

Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb.

AMPK protects endothelial cells against HSV-1 replication via inhibition of mTORC1 and ACC1.

Herpes simplex virus type 1 (HSV-1) is a widespread contagious pathogen, mostly causing mild symptoms on the mucosal entry side. However, systemic distribution, in particular upon reactivation of the virus in immunocompromised patients, may trigger an innate immune response and induce damage of organs. In these conditions, HSV-1 may infect vascular endothelial cells, but little is known about the regulation of HSV-1 replication and possible defense mechanisms in these cells.

Structure-function analysis of the AMPK activator SC4 and identification of a potent pan AMPK activator.

The AMP-activated protein kinase (AMPK) αβγ heterotrimer is a primary cellular energy sensor and central regulator of energy homeostasis. Activating skeletal muscle AMPK with small molecule drugs improves glucose uptake and provides an opportunity for new strategies to treat type 2 diabetes and insulin resistance, with recent genetic and pharmacological studies indicating the α2β2γ1 isoform combination as the heterotrimer complex primarily responsible. With the goal of developing α2β2-specific activators, here we perform structure/function analysis of the 2-hydroxybiphenyl group of SC4, an activator with tendency for α2-selectivity that is also capable of potently activating β2 complexes.

Novel dual-action prodrug triggers apoptosis in glioblastoma cells by releasing a glutathione quencher and lysine-specific histone demethylase 1A inhibitor.

Targeting epigenetic mechanisms has shown promise against several cancers but has so far been unsuccessful against glioblastoma (GBM). Altered histone 3 lysine 4 methylation and increased lysine-specific histone demethylase 1A (LSD1) expression in GBM tumours nonetheless suggest that epigenetic mechanisms are involved in GBM. We engineered a dual-action prodrug, which is activated by the high hydrogen peroxide levels associated with GBM cells.

Pd-Catalyzed Dearomative [3 + 2] Cycloaddition of 3-Nitroindoles with 2-Vinylcyclopropane-1,1-dicarboxylates.

A trans-diastereoselective Pd-catalyzed dearomative [3 + 2] cycloaddition between vinylcyclopropane dicarboxylates and 3-nitroindoles has been developed. The reaction provides densely functionalized cyclopenta[b]indolines with versatile vinyl and nitro-groups. The addition of a halide additive was found to be critical for the diastereoselectivity of the reaction, which is proposed to be a result of a rapid π-σ-π interconversion between the intermediates allowing for Curtin-Hammett control.

Correction: Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides.

Correction for 'Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides' by Yi Sing Gee et al., Org. Biomol.

Oxidative ring-opening of ferrocenylcyclopropylamines to N-ferrocenylmethyl β-hydroxyamides.

The in situ reduction of ferrocenyl cyclopropylimines to the corresponding amines triggers a facile oxidative ring-opening to yield the formal four-electron oxidation products: N-ferrocenylmethyl β-hydroxyamides. This process is believed to proceed via generation of a ferrocinium ion in the presence of air, leading to facile formation of a distonic radical cation that is ultimately trapped by oxygen.