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!

Blog Comments Back On Line

I was wondering why no one ever seems to comment on the blog posts anymore and just discovered that I no longer get notified when someone submits a comment. ARghhh. I am really sorry about this. I have been through the long list of comments (and spam) and have posted stuff from the last couple of years just now. In the future I will see them as they come in and post them straight away. As I have done in the past I will answer any (meaningful) questions that come in.

Happy Holidays to all Curly Arrow supporters. D!

The Antistatic Portal

For a change I had to leave the office, put on a lab coat and go to the lab to weigh out some compound. I had a nice fluffy freeze dried substance that had to be transferred from one vial to another. I was faced with usual static electricity problem. The easy solution is to take your plastic gloves off and hope that your compound doesn't fly around the hood when you try to transfer it. However, as often as not this will not do the trick. For the same reason the antistatic gun has been developed (see picture).

If you "shoot" your vials a couple of times this will help, sometimes, maybe. I find it a bit of a lottery whether this works even without gloves on. Which brings me to the point of this post, the Mettler Toledo™ U-shaped Ionizer Antistatic System or as I call it "The Antistatic Portal". It reminds me of the movie Stargate as it's standing there next to your balance humming with electricity (see picture below). Basically the idea is that you just move the stuff that is being weighed through the portal and voila the problem is solved without travelling to distant planets and fighting Egyptian Gods.

Pretty neat and the damn thing actually works with plastic gloves and all so I can recommend this addtion to your lab (if you can afford it). D!