Synthesis and Evaluation of a 2,11-Cembranoid-Inspired Library

The 2,11‐cembranoid family of natural products has been used as inspiration for the synthesis of a structurally simplified, functionally diverse library of octahydroisobenzofuran‐based compounds designed to augment a typical medicinal chemistry library screen. Ring‐closing metathesis, lactonisation...

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Bibliographic Details
Published in:Chemistry : a European journal 2016-04, Vol.22 (16), p.5657-5664
Main Authors: Welford, Amanda J, Caldwell, John J., Liu, Manjuan, Richards, Meirion, Brown, Nathan, Lomas, Cara, Tizzard, Graham J., Pitak, Mateusz B., Coles, Simon J., Eccles, Suzanne A., Raynaud, Florence I., Collins, Ian
Format: Article
Language:English
Subjects:
Benzofurans - chemistry
Biological Products - chemical synthesis
Biological Products - chemistry
Cancer
Chemistry
Chemistry, Pharmaceutical
Diterpenes - chemical synthesis
Diterpenes - chemistry
Inspiration
Lactones - chemistry
Libraries
medicinal chemistry
medium-ring compounds
molecular diversity
Natural products
oxygen heterocycles
Pharmaceutical industry
Screening
Small Molecule Libraries - chemistry
Solubility
Strategy
Synthesis
synthesis design
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Summary:The 2,11‐cembranoid family of natural products has been used as inspiration for the synthesis of a structurally simplified, functionally diverse library of octahydroisobenzofuran‐based compounds designed to augment a typical medicinal chemistry library screen. Ring‐closing metathesis, lactonisation and SmI2‐mediated methods were exemplified and applied to the installation of a third ring to mimic the nine‐membered ring of the 2,11‐cembranoids. The library was assessed for aqueous solubility and permeability, with a chemical‐space analysis performed for comparison to the family of cembranoid natural products and a sample set of a screening library. Preliminary investigations in cancer cells showed that the simpler scaffolds could recapitulate the reported anti‐migratory activity of the natural products. Building a bridge: A library of compounds based on the naturally occurring 2,11‐cembranoid family has been synthesised by using different synthetic strategies. The library was found to cover the space between the natural products and a screening library sample set (see figure). The new compounds were shown to recapitulate reported activities of the natural products.
ISSN:0947-6539
1521-3765
DOI:10.1002/chem.201505093