Simplified immunosuppressive and neuroprotective agents based on gracilin A.
Acetates
/ chemical synthesis
Cell Line, Tumor
Cell Membrane Permeability
/ drug effects
Crystallography, X-Ray
Cycloaddition Reaction
Diterpenes
/ chemical synthesis
Drug Design
Furans
/ chemical synthesis
Humans
Immunosuppressive Agents
/ chemical synthesis
Mitochondrial Membranes
/ metabolism
Molecular Conformation
Neurons
/ cytology
Neuroprotective Agents
/ chemical synthesis
Reactive Oxygen Species
/ metabolism
Structure-Activity Relationship
Journal
Nature chemistry
ISSN: 1755-4349
Titre abrégé: Nat Chem
Pays: England
ID NLM: 101499734
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
22
03
2018
accepted:
07
02
2019
entrez:
24
3
2019
pubmed:
25
3
2019
medline:
23
4
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30903037
doi: 10.1038/s41557-019-0230-0
pii: 10.1038/s41557-019-0230-0
pmc: PMC6532426
mid: NIHMS1521093
doi:
Substances chimiques
Acetates
0
Diterpenes
0
Furans
0
Immunosuppressive Agents
0
Neuroprotective Agents
0
Reactive Oxygen Species
0
gracilin a
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
342-350Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM052964
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134910
Pays : United States
Organisme : NIGMS NIH HHS
ID : R37 GM052964
Pays : United States
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