Andrei K. Yudin is in the Department of Chemistry at the University of Toronto and works on developing synthetic tools to study biological processes. Andrei was originally interviewed on Reactions in August 2011; given his recent paper in Nature Chemistry titled “Oxadiazole grafts in peptide macrocycles,” we thought we would check in and see what’s changed recently.
1. What has changed in your research since you last appeared on Reactions?
During my 2013 sabbatical, I got interested in protein crystal structure determination and the role of synthetic molecules in mediating this process. During that time, we initiated several projects that have led to the emergence of synthetic tools to develop molecular probes of protein function. This area of research is still in its infancy and we have yet to publish our results. But the tangible outcome has been profound: our interest in functional significance of molecules now influences the way we go about reaction design. I would not have predicted that structural biology could have a measurable bearing on how we attempt to innovate in chemical synthesis, but it sure does.
2. What do you think is the most important aspect of your recent Nature Chemistry paper?
This work has everything from an interesting mechanistic insight into how macrocycles are made to the ultimate application of our molecules. I think the capability to control the structure of macrocycles using oxadiazole grafts is something other labs will be able to use. I also hope that “the oxadiazole effect” will lead to the discovery of many other macrocyclic systems with controlled properties. As a result of our paper, Sigma-Aldrich is now in the process of manufacturing “Pinc”, the central reagent that enables our reaction to take place.
3. Which is your favourite element — or if not an element, favourite molecule and why?
Water is my favorite molecule and the reason is that it mediates interactions between small molecules and their protein targets. The ChemDraw-driven “language of chemical structures” is an unfortunate oversimplification. I wish we had an easy way to depict water surrounding chemical structures because it is water, in its bulk and structured states, which does the heavy lifting during biological interactions. Water networks shift, reorganize, and are even known to possess entropy/enthalpy compensatory mechanisms. These mechanisms influence the intended consequences of functional group placement when we, synthetic chemists, apply our “penetrating” insights and convince ourselves that we are engaged in molecular design.
4. Imagine that your inbox is empty, there is nothing in need of writing, and there are no experiments that need attention: how would you spend this free time?
I would play 18 holes at the Indian Wells Golf Club (Burlington, Ontario). I would do it two times in the same day – one from the white tees and one from the blue tees, although I am not sure there will be material change to my score.
5. If you were given $1 million as you stepped out of your office to do with what you will, what would you use it for?
I would start a company around our recent boron technology. This will allow us to make about 100 molecules and outsource phenotypic screening to a contract research organization. The strength of our yet-to-be-published chemistry is that the molecules are cell permeable. We can’t afford to run costly assays now, but with $1 million we will be in a good position to attract investors and do so on reasonable terms because the technology will be substantially de-risked by then.
6. Where would you most like to travel to, but have never been — and why?
I am interested in Labrador, a fascinating Canadian province I have never been to. It has breathtaking cliff views of the ocean and is known for its austere beauty. Unfortunately, this is not a place I could convince my wife to visit because there are no swimming opportunities, so I will have to wait for a conference to be held there.
7. Which chemist do you look up to most, living or otherwise — and why?
There are so many people I could name. Out of this list, I am drawn to those who did more with less. In this regard, I feel that Emil Fischer’s study of sugars is exemplary. Whenever I teach this topic, it sends chills down my spine. In his work, Fischer established the stereochemistry of sugars by studying epimerization between gluconic and mannonic acids. Doing this with the tools he had at his disposal was akin to a miracle.