Abbasov, Mikail E.Alvariño Romero, RebecaChaheine, Christian M.Alonso López, EvaSánchez, Jon A.Conner, Michael L.Alfonso Rancaño, María AmparoJaspars, MarcelBotana López, Luis MiguelRomo, Daniel2023-12-212023-12-212019Abbasov, M.E., Alvariño, R., Chaheine, C.M. et al. (2019). Simplified immunosuppressive and neuroprotective agents based on gracilin A. Nature Chemistry. 11, 342–350http://hdl.handle.net/10347/31628The architecture and bioactivity of natural products frequently serve as embarkation points for the exploration of biologically relevant chemical space. Total synthesis followed by derivative synthesis has historically enabled a deeper understanding of structure–activity relationships. However, synthetic strategies towards a natural product are not always guided by hypotheses regarding the structural features required for bioactivity. Here, we report an approach to natural product total synthesis that we term ‘pharmacophore-directed retrosynthesis’. A hypothesized, pharmacophore of a natural product is selected as an early synthetic target and this dictates the retrosynthetic analysis. In an ideal application, sequential increases in the structural complexity of this minimal structure enable development of a structure–activity relationship profile throughout the course of the total synthesis effort. This approach enables the identification of simpler congeners retaining bioactivity at a much earlier stage of a synthetic effort, as demonstrated here for the spongiane diterpenoid, gracilin A, leading to simplified derivatives with potent neuroprotective and immunosuppressive activityeng© The Author(s), under exclusive licence to Springer Nature Limited 2019Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/journal article10.1038/s41557-019-0230-01755-4349open access