Chemistry - A European Journal p. 5657 - 5664 (2016)
Update date:2022-08-03
Topics:
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
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.
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