Oxidative DNA damage is recognized by 8-oxoguanine (8-oxoG) DNA glycosylase 1 (OGG1), which excises 8-oxoG, leaving a substrate for apurinic endonuclease 1 (APE1) and initiating repair. Here, we describe a small molecule (TH10785) that interacts with the phenylalanine-319 and glycine-42 amino acids of OGG1, increases the enzyme activity 10-fold, and generates a previously undescribed β,δ-lyase enzymatic function. TH10785 controls the catalytic activity mediated by a nitrogen base within its molecular structure. In cells, TH10785 increases OGG1 recruitment to and repair of oxidative DNA damage. This alters the repair process, which no longer requires APE1 but instead is dependent on polynucleotide kinase phosphatase (PNKP1) activity. The increased repair of oxidative DNA lesions with a small molecule may have therapeutic applications in various diseases and aging.
Photochemistry is a fast growing research field and many transformations previously not accessible to chemists now have become part of an ever growing standard repertoire. The limiting factors for a photoreactor system however are the possibility to perform stirring, removal of excess heat and the irradiation with UV or visible light -all that within a secure surrounding. Systems for starters may be as expensive as several thousand Euro. Here we design and assemble a LED photoreactor using scrap and standard materials, spending less than 30 E for a LED. The system may be adjusted to any required wavelength and its assembly is shown for the use of a 400 nm LED. To demonstrate its application, we then exemplarily use the reactor in the removal of a photolabile protection group during the synthesis of a SARS-CoV-2 spike protein glycopeptide.
8‐oxo Guanine DNA Glycosylase 1 is the initiating enzyme within base excision repair and removes oxidized guanines from damaged DNA. Since unrepaired 8‐oxoG could lead to G : C→T : A transversion, base removal is of utmost importance for cells to ensure genomic integrity. For cells with elevated levels of reactive oxygen species this dependency is further increased. In the past we and others have validated OGG1 as a target for inhibitors to treat cancer and inflammation. Here, we present the optimization campaign that led to the broadly used tool compound TH5487. Based on results from a small molecule screening campaign, we performed hit to lead expansion and arrived at potent and selective substituted N‐piperidinyl‐benzimidazolones. Using X‐ray crystallography data, we describe the surprising binding mode of the most potent member of the class, TH8535. Here, the N‐Piperidinyl‐linker adopts a chair instead of a boat conformation which was found for weaker analogues. We further demonstrate cellular target engagement and efficacy of TH8535 against a number of cancer cell lines.
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