Friday, December 20, 2019

Bitopic Ligands and Epoxides

For most academics, research can be a somewhat slow process. From the conception of an idea to actually getting started can take a significant amount of time. The topic of this post started as an idea based on Dror et al.'s publication back in 2011 that provided some strong in silico evidence for the presence of so-called metastable binding sites (MBS). Explained in very basic terms the hypothesis is that ligands do not simply arrive in their binding pockets randomly but follow a path of low affininty binding sites that guide them to their destination. The report by Dror et al. provided some very compelling in silico evidence for the existence of MBS and planted the idea with us of making bitopic ligands that would simultanously target the orthosteric binding site (OBS) and a predicted MBS using the same pharmacophore. In principle this could lead to ligands with improved receptor subtype selectivity, higher affinity and slower off rates. We described the idea in a perspective paper in J. Med. Chem. in 2017 and you can also get a very basic idea of the principle in the figure below.

I was lucky enough to secure some funding from the Lundbeck Foundation Natural Sciences for developing these types of ligands back in 2015. A great funding scheme by the Lundbeck Foundation that they sadly stopped some years ago. Anyway, with the funding we managed to make this work take off and published our first paper on bitopic ligands this year in J. Med. Chem. From our study it is not clear if we have the predicted bitopic binding mode but we have some good indications that things are indeed working as hoped for. Even better we have another paper coming up in 2020 were we have very strong evidence for a bitopic binding mode with a MBS so I look forward to sharing that. The ligands that we synthesised in our paper were beta-blockers and they all have a classic beta-amino alcohol motif that is synthesised from glycidol as outlined below.
At first this may seem as a simple synthesis with a logical outcome. You activate the epoxide (optically active glycidol) with a sulfonyl leaving group, do a nucleophilc substitution with a phenolate, followed by ring-opening of the epoxide with isopropylamine. However, this only works with no stereochemical leakage thanks to Professor Barry Sharpless. In fact, it is rather tricky to make activated glycidol ring open strictly via a SN2 mechanism (= no stereochemical leakage) with no competitive SN2' reaction (= racemisation). Sharpless and co-workers solved this problem by screening various leaving groups and found that the meta-nosyl group did the trick. To my great pleasure Professor Erland Stevens from Davidson College noticed our publication and decided to use it for educational purposes posting a video on YouTube that explains the glycidol ring-opening reaction in detail. Great to see that our science can be used for educational purposes. D!

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