期刊
NATURE CHEMISTRY
卷 11, 期 4, 页码 342-350出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41557-019-0230-0
关键词
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资金
- NIH [R37 GM052964]
- NSF [CHE-1800411]
- Robert A. Welch Foundation [AA-1280]
- FEDER from CONSELLERIA DE Cultura, EDUCACION e ordenacion Universitaria Xunta de Galicia [2017 GRC GI-1682, ED431C 2017/01]
- Ministerio de Economia, Industria y Competitividad [AGL2014-58210-R, AGL2016-78728-R]
- EU [POCTEP 0161-Nanoeaters-1-E-1, Interreg AlertoxNet EAPA-317-2016, H2020 778069-EMERTOX]
- European Union's Seventh Framework Programme [312184 PHARMASEA]
- CDTI
- [ISCIII/PI1/01830]
- [RTC-2016-5507-2]
- [ITC-20161072]
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.
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