Winner: 2021 Organic Division Horizon Prize: Robert Robinson Award in Synthetic Organic Chemistry
Multidimensional Click Chemistry
For the development of multidimensional click chemistry, a next-generation click-technology that extends bond creation into the three-dimensional world, opening doors to new frontiers in biomedicine, materials science, and beyond.
A multidisciplinary collaboration has opened up a huge number of possibilities in synthetic chemistry through developing the technique of multidimensional click chemistry.
Click chemistry is a method of synthesising larger molecules by combining smaller 鈥渕odular鈥� chemicals together 鈥� similar to how Lego bricks might 鈥榗lick鈥� together. The click reaction utilises only the most perfect reactions, meaning they occur quickly and irreversibly with minimal by-products created. Until recently, these connections were predominately flat (2-dimensional) and limited to uniting two modules.
This led the team to investigate using a new click 鈥榗onnecting hub鈥� 鈥� thionyl tetrafluoride gas (SOF4). This 鈥榟ub鈥� molecule was first reported in 1902 and has four replaceable fluoride sites for nucleophilic 鈥榩lug-ins鈥�, which allows for complex molecules to be assembled by a 3D connector. Through developing a catalytic sulphur fluoride exchange (SuFEx) system, the team developed a viable method for making high quality 3D compounds by displaying modular 鈥榩lug-ins鈥� around tetrahedral sulphur 鈥榟ubs鈥� using click chemistry.
The potential applications of multidimensional click chemistry are numerous because the technology serves as an 鈥榚nabling tool鈥� to access a much larger chemical world. One important application includes drug discovery - using SOF4, a panel of 460 derivatives were made overnight from a weak antibiotic. From these derivatives, a stronger antibiotic rapidly emerged which inhibits a bacterial enzyme with 480-fold higher potency.
In addition to drug discovery, other implications include chemical biology and materials science.
It felt like things had finally clicked into place.
John Moses
Grant A. L. Bare, Former Postdoctoral Associate, Scripps Research
Rachel C. Botham, ACS postdoctoral fellow, Scripps Research
Gabriel J. Brighty, Graduate Student, Scripps Research
John Cappiello, Lab Manager/ Staff Scientist, The Scripps Research Institute
Xiaoyan Chen, Undergraduate student, Sun Yat-Sen University
Emily Chen, Research Scientist, Calibr at Scripps Research
Xuemin Chen, Graduate Student, Peking University
Nicholas Dillon, Postdoctoral Researcher, UCSD School of Medicine
Jiajia Dong, Research Professor, Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Hafedh Driss, Associate Professor, Department of Chemical and Materials Engineering, King Abdulaziz University
M. G. Finn, Professor and Chair, Georgia Tech
Bing Gao, Professor, Hunan University
Bruce D. Hammock, Distinguished Professor, Department of Entomology & UCD Comprehensive Cancer Center
Mitchell V. Hull, Director, HTS, Calibr at Scripps Research
Jeffery W. Kelly, Professor, Scripps Research
Hyunseok Kim, Postdoctoral Associate, Scripps Research
Seiya Kitamura, Postdoctoral Associate, Scripps Research
Shinichi Kitamura, Professor, Osaka Prefecture University
Cathy Klasen, Lab Admin Coordinator, Scripps Research
Liana M. Klivansky, Principal Scientific Engineering Associate, Organic and Macromolecular Synthesis, The Molecular Foundry, Lawrence Berkeley National Laboratory
Hartmuth Kolb, Head of Research, Johnson & Johnson
Miyako Kotaniguchi, Project Researcher, Osaka Prefecture University
Larissa Krasnova, Staff Scientist, Johnson & Johnson
Gencheng Li, Graduate Student, Scripps Research
Suhua Li, Professor, Sun Yat-Sen University
Dong-Dong Liang, Postdoc, Lab of Organic Chemistry, Wageningen University
Feng Liu, Associate Professor, Fudan University
Yi Liu, Facility Director, Organic and Macromolecular Synthesis, The Molecular Foundry, Lawrence Berkeley National Laboratory
Jianmei Lu, Professor, Soochow University
Christophe Morisseau, Professional Researcher, University of California Davis
David E. Mortenson, Postdoctoral fellow, Scripps Research
John E. Moses, Professor, Cold Spring Harbor Laboratory
Luke Nelson, Technician, Scripps Research
Victor Nizet, Distinguished Professor, UCSD School of Medicine
Gao Ping, Sci Admin, Shanghai Institute of Organic Chemistry
Sidharam P. Pujari, Research Associate, Lab of Organic Chemistry, Wageningen University
K. Barry Sharpless, Professor, Scripps Research
Janet Sharpless, Collaborator, Independent
Angelo Solania, Postdoctoral Associate, Scripps Research
Chu Wang, Professor, Peking University
Hua Wang, Director, Sorrento Therapeutics Inc.
Jordan L. Woehl, Postdoctoral Fellow, Scripps Research
Dennis Wolan, Associate Professor, Scripps Research
Peng Wu, Professor, Scripps Research
Qinheng Zheng, Postdoc Scholar, University of California, San Francisco
Feng Zhou, Postdoc Scholar, Soochow University
Han Zuilhof, Chair of Organic Chemistry, Wageningen University, Tianjin University, King Abdulaziz University
Q&A with Multidimensional Click Chemistry
John Moses: Professor, Cold Spring Harbor Laboratory
How do you see this work developing over the next few years / what is next for this technology?
Probably the biggest impact of this chemistry will be to enable others to make discoveries which I think click chemistry did with the original CuAAC reaction - it was enabling technology.
What does good research culture look like or mean to you?
Research can be hard work 鈥� whether it鈥檚 good chemistry or not 鈥� it still takes a lot of effort, you have to spend hours in the lab so enthusiasm to do that, along with having a goal is good research culture. It鈥檚 also important to be open minded 鈥� don鈥檛 say no. If a student has an idea, let them do it, and they will flourish that way.
What's the importance of collaboration in the chemical sciences?
Click chemistry is a discovery method driven by the reliable formation of robust connections, but this also extends beyond molecules, where connecting key people and collaborators are equally important.
In the same way that different fragments contribute unique properties to the molecules they form, each collaborator brings their own individual vision and skills to a project.
A good example is in our recent development of the SOF4-derived polymers. The SuFEx chemistry that Suhua Li developed allowed us to make quite special polymers. Still, as synthetic chemists, we had no firm idea about the structure of these materials until Han鈥檚 team (Netherlands, China, and Saudi Arabia) used their skills and techniques to elucidate the material鈥檚 helical form.
The extra bonus is that you also get to hang out with amazing people like Barry....
Barry Sharpless: Professor, Scripps Research
How do you see this work developing over the next few years / what is next for this technology?
Bacteria don鈥檛 make mistakes until they're dying, then they make a hell of a lot of mutations. In comparison, viruses are sloppy the whole way through and are constantly mutating. So we have to be right behind them 鈥� they mutate, that鈥檚 fine, we mutate too. We can change one group in our recipe for a treatment, and we鈥檝e got another compound. That鈥檚 what we think will happen 鈥� and there鈥檚 no reason why not. The compounds are not going to be suddenly toxic just because one little group was changed, so we have got to be fast. Quickness is needed, especially with things like cancer, which mutates like crazy. An individual patient might need a particular twist on their drug and it could even be that easy 鈥� we could sample a few different versions of a drug and see which would give them the most effect.
What advice would you give to a young person considering a career in chemistry?
You're not confident when you're young 鈥� I wasn't and I had to prove myself as I felt insecure. I always take a risk and that's probably my saving grace, but I think most people have learned that do 鈥榝ancy鈥� things and to try and be elegant and impressive when you write about it, but actually, the more elegance you have in your paper, then the more trouble you're in because you spend a lot of time being proud of the development of something which may be a curiosity. It鈥檚 always good to be moving on, no matter how successful you are at something, you need to have a drive to move on. I always move on for re-activity鈥檚 sake 鈥� I鈥檓 always looking for that perfect reaction, and that鈥檚 probably been my biggest strength.
What's the importance of collaboration in the chemical sciences?
If you want to learn, you certainly don't want to do your postdoc research for somebody in the same field as your initial training 鈥� that is not a good idea and just shows how political people have become. You want to collaborate with people in totally different fields 鈥� like chemical engineers, polymer science or in biology. There is a new generation coming up and these young people are going to teach others to find collaborators in different fields. I used to visit all the labs at Stanford that my friends were in and I would ask them what they were doing. They would tell me all about their project and next thing you know, two graduate students have solved each other鈥檚 problems, because I knew something they didn鈥檛 know, and vice versa. Once you鈥檙e good at something, use what you鈥檙e good at, but don鈥檛 concentrate on it.
Qinheng Zheng: Postdoc Fellow, University of California, San Francisco
What inspires or motivates your team?
We are largely influenced by the old German chemistry, especially those reactions and procedures documented in the 40-volumn Houben-Weyl Methoden der Organischen Chemie. In our team, Prof. Sharpless with his experience and expertise has been an inspiration.
How are the chemical sciences making the world a better place?
Chemistry is at the centre of natural and applied sciences. The breakthroughs in chemistry have brought medicines and polymers to the world. The rapidly growing applications of our multidimensional SuFEx click chemistry in drug discovery and materials science is a perfect reflection of the contributions of chemistry to the world in general. We anticipate that the development of multidimensional SuFEx click chemistry will make new medicines more affordable and their discovery faster.