Bioorganic & Medicinal Chemistry Letters最新文献

The Werner protein, WRN, is a member of the RecQ helicase family implicated in genome maintenance. Several large-scale functional genomics screens have identified WRN as a synthetic lethal target in cancer cell lines with microsatellite instability-high (MSI-H). Accordingly, WRN is considered a potential therapeutic target in MSI-H cancers. HRO761, a non-covalent WRN inhibitor developed by Novartis, entered clinical trial for patients with MSI-H colorectal cancer (CRC). In this study, we investigated bioisosteric replacement of the hydroxyl pyrimidine residue of HRO761 with several bicyclic structures to obtain a novel chemical entity. In vitro ATPase and cell proliferation assays revealed two candidate chemicals that showed similar or better effects than HRO761. Additionally, an in vivo study demonstrated that KWR095, a newly synthesized WRN inhibitor, has significant anti-proliferative effects compared with vehicle.

Changes in metabolism are associated with several prevalent and rare diseases, like Hunter syndrome (MPS II). These alterations result in changes in mitochondrial function, therefore having non-invasive imaging biomarkers to detect this pathophysiological hallmark is a key objective of translational medicine. Here we report the synthesis and in vivo evaluation of the [¹⁸F]berberine analogue ([¹⁸F]BEAN), in both wildtype animals and a mouse model of Hunter's disease. PET/CT imaging revealed that [¹⁸F]BEAN could detect mitochondrial dysfunction in the heart, liver, and brain of Hunter's disease (Ids KO) mice. These data suggest that [¹⁸F]BEAN may be a viable translational PET biomarker for the imaging of diverse pathologies that have impaired mitochondrial function.

A bifunctional ligand is an essential component for targeted cancer therapy using cytotoxic radionuclides. We report the synthesis and evaluation of a novel bifunctional ligand, 3o-C-NETA, designed for labeling a bioactive small molecule or an antibody with β-particle emitting radionuclides ⁹⁰Y and ¹⁷⁷Lu. 3o-C-NETA is an octadentate chelating agent and contains both a macrocyclic backbone (1,4,7-triazacyclononane, TACN) and pendant donor groups. 3o-C-NETA was efficiently synthesized via the regiospecific ring opening of a functionalized aziridinium ion with tert-Butyl protected NODA (1,4,7-triazacyclononane-1,4-diacetic acid) and evaluated for radiolabeling kinetics and in vitro complex stability with ⁹⁰Y and ¹⁷⁷Lu. The new bifunctional ligand (3o-C-NETA) rapidly bound to ⁹⁰Y or ¹⁷⁷Lu, and the corresponding ⁹⁰Y- or ¹⁷⁷Lu-labeled 3o-C-NETA remained stable in human serum for two weeks.

The molecular beacon (MB) strategy finds diverse applications in bioimaging, biosensing and disorders diagnostics. Classical MBs are loop-stem hairpin oligonucleotides modified with a reporter and a quencher at the 5'- and 3'- ends. Hybridization with a specific target leads to spatial separation of the quencher and the reporter with subsequent changes in spectral signal, for example, an increase in reporter fluorescence emission. However, hydrophobic interactions between a convenient bulky quencher and the reporter might influence hybridization properties and limit stem length in MB design. In this work, we studied the synthetic nucleobase analog tC^o_Azo mimicking cytosine, capable of quenching reporter (FAM) fluorescence in folded MBs while minimally affecting their stability compared to MBs with classical FAM/BHQ1 labels. In addition, we conducted a preliminary assessment of the applicability of FAM/tC^o_Azo-modified MBs for SERS-based techniques using short single-stranded and long double-stranded DNA fragments from Fusarium avenaceum elongation factor 1a DNA as matrices. SERS intensity was decreased in the presence of matrix DNA compared to the scrambled sequence; and the MB modified with three tC^o_Azo residues provided concentration-dependent signal. The results indicate that tC^o_Azo is a promising tool for fine tuning MB properties for fluorescent- and SERS-based diagnostic applications.