Iminothioindoxyl (ITI) switch one year later

A year ago, our first ITI paper was published in Nature Communications and here we look back at what it meant for our lab and the fantastic network of collaborations it brought together.

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Four years ago, in our young group an idea emerged to increase the solubility of hemithioindigo photoswitches by replacing the central C=C double bond with a C=N one. The idea was tried, the compound showed no switching and went to the shelf. Three years ago, our collaborators, who work on ultra-fast spectroscopy, offered to take another look at it. A mere year later (things move fast in science!) we got around to sending the compound all the way to their laboratories in Amsterdam (2 h traveling time by train from our labs in Groningen, we could have done this a bit earlier…). And then the story of iminothioindoxyl (ITI) switch really begun, followed a year later by the first publication.

For me personally, our ITI story was the first “big” paper published in my independent academic career. The dream behind our work is to introduce light-based therapeutic and imaging modalities to the clinics. Light is a great control element in biology, as it interacts with it in a limited way (until kindly asked to do so with molecules we design) and can be delivered with high precision in space and time. And so many inventive methods have been recently introduced to deliver light into the human body! The technology is there, the pharmacology and molecular biology as well – now it is time we deliver molecules that will bridge those disciplines along the principles of photopharmacology. In this context, molecules that can transform photonic input into a clinical output stand central. For controlling biological systems with light, having our “own” photoswitch that responds to visible light offers a great molecular tool; Our Nat. Comm. paper has definitely shaped the interests in my group towards discovering and understanding such visible light photoswitches and its impact on what we do will be clear for many years to come…

We were overwhelmed by the response to the manuscript. It got write-ups in, science daily,, and many others. It also helped us present our work to a broader public, with Mark Hoorens (the first author of ITI story) being interviewed for the Dutch radio and our story being covered in a two-page article in a national newspaper. But the most important aspect that emerged from this work is a wonderful network of friends, who are trusted collaborators with whom we share all our results, successes, questions, doubts and frustrations.

If you look for a story on how a molecule can connect people – look no further.  Ever since our collaborative work on DASA switches, compounds synthesized and roughly evaluated in Groningen (NL) are immediately sent to the laboratories of Wybren Jan Buma (Amsterdam, NL) and Mariangela Di Donato (Florence, IT) for advanced spectroscopy measurements. At the same time, they are being analyzed using TD-DFT by Miroslav Medved’ (Olomouc, CZ) and Adèle D. Laurent (Nantes, FR), whose calculations help us understand the experimental data and inspire new designs. These interwoven paths of molecular design, synthesis, spectroscopy and in silico calculations are leading us further down the path of discovery, even in the times where research time is especially precious. Despite COVID lockdowns, lab shift-work, this collaboration network operates and meets online, exchanging ideas, data, and stories from all over Europe, hoping to meet again in person one day and pushing forward to further improve ITI.

In those pressing times, an exciting and friendly network of this kind is priceless… and it makes us think of the amazing places it brought us to when traveling was still possible! We successfully presented ITI at Gordon Research Conference in Holderness (US) and 2019 ISOP conference in Paris (FR), and Mark got to spend three weeks working in the lab in Florence on an invitation from Mariangela, working on picosecond spectroscopy.

And there is still a lot to do! A new molecular photoswitch always provides us with surprises and challenges. What especially drives us now is the need to extend the thermal stability of the metastable E-ITI isomer. With the initial design, we were in the microsecond regime. Our great friend and recently also collaborator Prof. Drew Woolley from the University of Toronto tells us  that the best half-life for a photopharmacological agent lies in the 0.1-10 second region, meaning that we need to cross 2-3 orders of magnitude in thermal stability… watch this space in the future to see if we succeed!

Wiktor Szymanski

Associate Professor, University Medical Center Groningen

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