Marine Natural Products as Nrf2 Modulators: Reconsidering the Relationship Between Electrophilicity and Nrf2 Activation

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in cellular protection against oxidative stress. The electrophilicity of Nrf2 activators has been suggested to contribute to Nrf2 activation through modification of reactive cysteine residues in Kelch-like ECH-associated protein 1 (Keap1). However, relatively few Nrf2 activators have been identified from marine natural products, and the extent to which electrophilicity explains their Nrf2 activity remains unclear. In this review, I examine the relationship among marine natural products, the Keap1–Nrf2 pathway, and electrophilic chemistry, with emphasis on electrophilic structural motifs and computational descriptors. Selected marine natural products were compared using frontier molecular orbital parameters, global electrophilicity, and the total-energy-based ΔSCF approach, together with experimentally reported Nrf2-related activities. The comparison indicates that global electrophilicity is a useful chemical descriptor but does not necessarily predict Nrf2 activity. Compounds with relatively low global electrophilicity can exhibit Nrf2-related activity, while metabolic or oxidative transformation may generate bioactive species with properties different from those of the parent compound. I propose an integrated strategy combining electrophilicity, local reactivity, reaction-site accessibility, metabolism, intracellular exposure, and biological assays for the discovery and prioritization of Nrf2-modulating marine natural products.