Dichlorophenylacrylonitriles as AhR Ligands – Targeting breast cancer

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    In a fascinating paper recently published in ChemMedChem, Prof. Adam McCluskey and a team of collaborators from Newcastle, Australia and West Lafayette, USA have used a Vapourtec easy-Photochem and UV-150 photochemical reactor to perform a photo-bromination in continuous flow, of a highly promising series of anti-cancer compounds.

    A Knoevenagel condensation of dichloro phenylacetonitriles enabled the team to prepare a library of dichlorophenylacrylonitriles, two of which in particular showed high potency and selectivity for a specific line of breast cancer. In the detailed and highly informative paper, McCluskey and the team explain some of the context of these compound’s activity, and describe a series of modifications carried out in an attempt to enhance their activity or selectivity.

    One key aspect is the compounds solubility; inclusion of bromine moieties was expected to result in an improvement. Using the Vapourtec easy-Photochem with a UV-150 photochemical reactor, a bromination using NBS was carried out with a range of the different filters offered by Vapourtec and at 0 °C. Excitingly, the team found that filter choice had a direct impact on the selectivity of the bromination; using filter 1 produced a mixture of both mono-brominated products, but using filter 2 produced predominantly the 2-bromo, while filters 5 and 6 produced mostly 3-bromo products. The same influence on selectivity was observed for the di and tri-bromo analogues as well.

    This is an important demonstration of how wavelength control can greatly impact a reaction. The UV-150 flow photochemical reactor can be equipped with a variety of filters to enable the user to target specific wavelength ranges. The newly brominated compounds showed a 3-fold increase in solubility compared to the non-brominated analogues, albeit with a small loss in potency.

    The team explored modifying the general scaffold of the compound by the addition of a nitro group, and a further, nitro example was photo-brominated using the easy-Photochem and UV-150 to again improve solubility, however this resulted in a 2.5 fold reduction in the compounds potency.

    “This is a truly fascinating paper” says Dr Ryan Skilton, research scientist at Vapourtec, “beyond a synthetic chemistry paper, the context that the team give regarding the drug activity provides a real insight into the function of these compounds. Vapourtec’s UV-150 photochemical reactor was designed to be quick and easy to use, and being able to change filters so readily has enabled quite targeted syntheses of the specific brominated analogues of these compounds. We can’t wait to see what Professor McCluskey and the other specialists on this paper are able to achieve next.”

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