RT Journal Article
T1 Simplified immunosuppressive and neuroprotective agents based on gracilin A
A1 Abbasov, Mikail E.
A1 Alvariño Romero, Rebeca
A1 Chaheine, Christian M.
A1 Alonso López, Eva
A1 Sánchez, Jon A.
A1 Conner, Michael L.
A1 Alfonso Rancaño, María Amparo
A1 Jaspars, Marcel
A1 Botana López, Luis Miguel
A1 Romo, Daniel
AB The 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 activity
PB Nature Research
YR 2019
FD 2019
LK http://hdl.handle.net/10347/31628
UL http://hdl.handle.net/10347/31628
LA eng
NO Abbasov, M.E., Alvariño, R., Chaheine, C.M. et al. (2019). Simplified immunosuppressive and neuroprotective agents based on gracilin A. Nature Chemistry. 11, 342–350
NO The authors acknowledge support from the NIH (R37 GM052964 to D.R.), NSF (CHE1800411, to D.R.) the Robert A. Welch Foundation (AA-1280 to D.R.), FEDER co-fundedgrants from CONSELLERIA DE Cultura, EDUCACION e ordenación UniversitariaXunta de Galicia (2017 GRC GI-1682, ED431C 2017/01), CDTI and TechnologicalFunds, supported by Ministerio de Economía, Industria y Competitividad (AGL2014-58210-R, AGL2016-78728-R, AEI/FEDER, UE) (to L.M.B.), ISCIII/PI1/01830 (to A.A.)and RTC-2016-5507-2 and ITC-20161072, from EU POCTEP 0161-Nanoeaters-1-E-1,Interreg AlertoxNet EAPA-317-2016 and H2020 778069-EMERTOX (to L.M.B.) andfrom the European Union’s Seventh Framework Programme managed by the ResearchExecutive Agency (FP7/2007-2013 under grant agreement 312184 PHARMASEA toL.M.B. and M.J.). N. Bhuvanesh and J. Reibenspies (Center for X-ray Analysis, TAMU)secured X-ray data and W. Russell (Laboratory for Biological Mass Spectrometry,TAMU) provided mass data. Correspondence and requests for materials should bedirected to D. Romo (chemistry) and L. Botana (biology).
DS Minerva
RD 24 abr 2026