There is no doubt that one of my favourite experiences is when we get to train undergraduate students in our lab. This Summer we hosted Joanne Tan and Sonia Zaichuk. Joanne is an undergrad from McMaster, whereas Sonia is from U of T. Yesterday we had a Summer poster session sponsored by AstraZeneca (an annual event when our students present their results) and… both Sonia and Joanne were among the prize winners!
The whole lab was really proud of them. I personally derive the biggest satisfaction from the following: typically I get to see and correct students’ posters but now that I am on sabbatical I suppose people think I do not have time. So… I did not see the posters! It is really cool that the ladies (under the guidance from Ben Chung and Serge Zaretsky, their immediate advisors) displayed a really high caliber of scholarship and presented their work in the best possible way. Kudos to them as well as to Serge and Ben!!
Ever since my lab identified aziridine aldehyde dimers in 2006 and termed them “kinetically amphoteric molecules”, we have been searching for new examples of this privileged, yet strange, class of compounds. Of course, we have also paid close attention to other researchers’ efforts in uncovering cases of amphoteric reactivity!
I have been really intrigued by Professor Sun’s oxetane aldehydes. Here is an example of an efficient [6+2] cyclization with siloxy alkynes giving rise to the first intermolecular synthesis of eight-membered lactones.
There are two pathways (a and b) that are being considered by the authors:
Drawing on their initial discovery, Sun and co-workers later expanded the utility of oxetane aldehydes to multicomponent reactions. Thus, the oxetane ring was shown to be a superb directing group that played a crucial role in achieving both high yields and high enantioselectivities in amphoteric molecule-driven multicomponent reactions. I will continue paying attention to advances in this area…
Below is one of my favourite quotations and I hope you like it. I think that my recent experience with getting macrocycle crystals together with my students underscores the notion that, at some point, we just need to drastically increase the number of experiments we can run and analyze. Effectively, what Elena and I have been doing with protein crystal structures, can (and should) be applied to other molecules which are tricky to crystallize. We have shown that the SGC platform is adaptable to other scenarios and I will continue our work along these lines of screening. Dr. Paul Reider (Merck) told me once that at least 10% of a researcher’s work should be aimed at science that is not hypothesis-driven but is Edisonian. I concur: this is what we should do more of. Nature is just too complicated.
This is a happy day for us because one of the architecturally complex macrocycles we have been working on succumbed to crystallization and diffracted really well. I am showing the main parties to this feat: Joanne Tan (an undergraduate student from McMaster who has been doing a great job with us over the past 3 months as part of her NSERC-funded Summer research position), Jen Hickey (Jen is working with Encycle) and Serge Zaretsky (my PhD student). Hats off to these guys for making the molecule. Importantly, we were able to show that we can employ protein crystallization conditions in order to get perfect (you can see) crystals of significantly smaller molecules (in this case – medium-sized macrocycles). I am amazed by the power of this method as we only needed 2 mgs to screen 96 crystallization conditions! If you do the math, crystals in the two wells that you see below (each well is 3 mm in diameter) came from 0.02 mgs of material in each case. Powerful stuff. Alan Lough has solved this structure (and we are working on another one with Aiping Dong from SGC, who is very excited about the project).
Sorry that I cannot show you the structure in full – I don’t want to jeopardize the publication. You will see why. One of these days.
Cross-fertilization between biology and chemistry is in action!
Elena and I ran insect protein expression of a secreted protein that is heavily post-translationally modified. It was particularly cool to count cells with a little counter device (I felt like a bouncer in the club)… This system is tougher than E.coli, no doubt. We did isolate some good stuff off the Ni bead column. We’ll purify it tomorrow. After that I spent some time with Gena Poda at OICR who taught me docking. I am loving this experience – I get to learn the whole process of probe development, from cloning to expression and modelling.
Later on, thanks to Jeff St. Denis (my PhD student), we had a trip to the Oakland A’s/Blue Jays’ game. Jeff bought the tickets and we all had a blast. Here is a pic (about half of my lab was able to come). Below you see Joy, Jeff, Megan, Shinya, Chris, Sean (top row); Sonia, Ben (bottom row). I hope we do it more often while the weather is still good (maybe a bbq at my place, eventually?)…
I was looking through some old photos and found this one from 1999!
From left to right: Alicja, Agniezhka, Juan, myself, Shahla, Omar, Jim, Tung, and Raju. Alicja, Juan, Omar and Agniezhka were among my first undergraduate students. Shahla, Jim, and Tung were my first graduate students and Raju – my first postdoc. Out of this great group of people I see Raju a lot these days. He works at OICR (Ontario Institute for Cancer Research) and is doing great. We should have a reunion with everyone at some point… Hope everyone else is doing well, although people scattered are all over the place (more on that later).
We all got this really sad news earlier today: Professor Tony Pawson of Mount SInai has died.
Tony was one of the titans in the field of cell signalling and, in fact, one of the founders of this field. My own interest in pursuing disrupters of protein-protein interactions was, to a large extent, based on my interactions with Tony. Over the past three years Tony, Shawn Li, Jeff Wrana, and I have shared an ORF grant aimed at finding specific protein domain ligands. We will dearly miss Tony and his insights.
I am certain that my lab and I will take his legacy as an inspiration to go forward and continue pursuing science at the chemistry/biology interface. Ironically, today (as part of my sabbatical work at SGC) we got our second protein crystal (thanks a lot to Elena and Aiping, again!!!) and this is one of the ones Tony was really keen on. Below are the views and the crystal structure that shows (in yellow) the two aromatic cages that recognize lysine-containing fragments. We will remember Tony dearly and will work tirelessly toward some of the common goals we have shared…
Apparently, my PhD student Serge Zaretsky is not great at soccer… He emailed me yesterday from the Colby Sawyer College, where he is attending the Gordon Conference (Medicinal Chemistry). Those industry people (who form the majority of attendees at this GRC) are just too good… However, and more importantly, Serge got one of three poster awards and will present his work as a short talk tomorrow morning in front of the world’s leading medicinal chemists. It seems that there is a lot of interest in macrocycles (Serge’s area of expertise). No pressure there, Serge! Good luck!
The lads (Serge Zaretsky and Adam Zajdlik) are at the Gordon Conference on Medicinal Chemistry this coming week. I am really looking forward to hearing how their research has been received. They both have really cool stories centred around boron-containing heterocycles and their biology (Adam) and peptide macrocycles made with our evolving aziridine aldehyde methods (Serge). It is almost 9pm now and I think I know where they are going to be soon after the talks are done! Below are Serge’s and Adam’s pics and a couple of snip bits about some of the science they are presenting.