Serotonin derivatives as organocatalytic switches of 8-oxoguanine DNA glycosylase OGG1

DNA serves as the blueprint of life on Earth. Yet, its integrity is constantly threatened by endogenous and exogenous factors. To counteract this, cells rely on a range of DNA repair pathways, which have been the subject of extensive studies. Historically, efforts to modulate DNA repair for therapeutic benefit have focused on classical approaches, such as the inhibition of DNA repair proteins, particularly in repair-deficient cancers. An alternative concept, first introduced in 2003 and further developed in recent years, involves small molecules that enhance DNA repair by acting as organic co-catalysts for the DNA repair enzyme 8-oxoguanine glycosylase 1 (OGG1). These compounds, termed organocatalytic switches (ORCAs), enable OGG1 to act as an AP-lyase in addition to its native glycosylase activity, accelerating DNA repair. To date, only a limited number of ORCA scaffolds have been explored. The research reported herein describes the lead optimisation of a novel series of ORCAs derived from a serotonin-based hit compound identified via high-throughput screening and early-stage optimisation. A synthetic route centred on the Pd-catalysed Larock indole synthesis enabled the construction of a library of 2- and 3-arylated serotonin derivatives. Biochemical data, supported by crystallographic and computational docking studies, guided the rational design of more potent analogues. Ultimately, over a tenfold increase in potency over the original hit was achieved. Finally, a set of mechanistic probe compounds were prepared to investigate the mode of action of serotonin-based ORCAs. While a definitive mechanism could not be established, the evidence supports active-site binding and is consistent with a water-mediated AP-site cleavage pathway.