Trinity Hall’s Dr Nelson Lam is an author on a new paper which shows how scientists hope new techniques can help make editing molecules as simple as editing documents, allowing for quicker and cheaper drug manufacturing. He spoke to us about the research and its potential applications.
What was your research about?
Organic molecules (molecules built from carbon, hydrogen and often oxygen and nitrogen) underpin processes that are vital to life. By default, the core skeletal structure of organic molecules are capped with inert carbon-hydrogen (C–H) bonds—and there are a lot of them in a given organic molecule.
While the core structure is important, it is their appendages (termed functionalities, which typically contains a complex set of atoms) that make it useful for diverse applications. One notionally direct way to achieve this is to ‘activate’ inert C–H bonds (C–H activation) so that useful functionalities can be installed. This is much easier said than done; the intrinsic strength and ubiquity of C–H bonds mean that we need to figure out how to break these strong C–H bonds (the “reactivity challenge”) and to do this at one specific site out of many (the “selectivity challenge”).
Aza-arenes are a prevalent class of organic scaffold often seen in drug molecules—for example, they form the core of camptothecin (anticancer) and chloroquine (antimalarial). Building on our prior research, we know that if we could position a palladium catalyst next to a target C–H bond, then we could boost the catalyst’s reactivity to break C–H bonds at that specific site. This effectively allows us to “edit” a specific C–H bond while leaving the rest of the molecule untouched
In this work, we developed two “catalytic directing templates” to activate two previously-inaccessible C–H bonds on aza-arenes. These work by first binding to aza-arenes, while recruiting the palladium catalyst next to a target C–H bond. This method completes the suite of chemical reactions required to directly “edit” aza-arenes at any position, and we demonstrated that we could start from the simplest aza-arene (quinoline) as well as complex pharmaceutical agents and generate diverse analogues in short C–H editing operations.
What does this mean for the development of new drugs?
A big aspect of modern medicine revolves around the discovery and development of new organic molecules to curb disease states by binding/modulating the relevant biological targets. Part of this involves “hit to lead optimisation”, where the properties of a promising organic molecule drug candidate gets refined further (to, for example: minimise toxicity; increase potency; or improve physical properties). In an ideal world, we would take the promising structure and “directly edit” at the relevant positions to install the right things at the right place—much like proof reading in a Word Processor where you edit words directly to make a paragraph stronger.
This concept of “molecular editing” is much easier said than done. Traditionally, this was seen as an insurmountable challenge; even at the turn of the millennium chemists have referred to this challenge as the “Holy Grail” of organic chemistry. As a consequence, drug development (or indeed any field that requires structural optimisation of organic molecules) means that for every structure a chemist drafts up for optimisation, a new chemical synthesis often needs to be carried out from scratch, however structurally similar these compounds may be. Often this is done just to include a single point of difference in the end-product; the analogy here would be requiring the user to rewrite the document from start-to-finish just so a single word can be changed.
Our report shows that a “click and edit” word-processor-like operation can be achieved for aza-arene scaffolds, which we think could expedite the discovery and optimisation of these ubiquitous structures in drug development. Indeed I know that my previous lab currently has a lot of fruitful collaborations with chemical biologists to use this new technology to access previously-inaccessible drug analogues.
While we still have a very long way to go towards achieving the vision of “universal molecular editing”, this latest report show and show that such a “Holy Grail” operation is both possible and increasingly practical to do so.
Did you and your colleagues have a “eureka” moment with this research?
Yes and no. Our report comes from over a decade’s worth of cumulative insight (and a lot of hard work!) on addressing both the reactivity and selectivity challenge that underpin C–H activation. For example, the “catalyst positioning” hypothesis so crucial for the success of this work was proposed in 2012. Iterative validation of this proposal led us to further distil this down this down to “distance” and “geometry” of catalyst positioning relative to both the C–H bond and an ‘anchored/fixed point’ of a molecule. At the start of this project, these concepts were only vaguely described, and it was through incrementally working on this project that led us to suspect that there were hidden patterns that could help guide us towards solving this problem. This also led us to publish another report describing exactly how important “distance” and “geometry” is to our catalyst positioning hypothesis.
However, there were two key advances in this work that resulted from “Eureka” moments. Dr Keita Tanaka discovered that the “directing template” used to recruit both the aza-arene and palladium catalyst could be rendered catalytic, allowing much smaller quantities to be used without sacrificing reaction efficacy. Along with driving the project, the lead author of this work—Dr Zhoulong Fan—made the insightful discovery that a technique called “chirality recognition” could refine site-selectivity and single out a C-H bond for targeting. Without this critical insight, the selective activation of one particular aza-arene C–H bond in this paper would not have been possible.
How does it feel to be involved in research that is published in Nature, one of the world’s leading research publications?
I am very happy that the team is recognised for the incredible amount of work that went into this work. Because Nature is such a visible platform, we will be particularly excited to see this work applied by the wider community—I’d be very happy if people reading our research outside of our immediate field could then apply our findings to quickly solve a tricky or labourious synthesis problem! More importantly, we hope that the visibility of this research spurs further research in the sphere of selective molecular editing.
Have you taken anything else away from this research?
One of my personal takeaways from being involved in this project is to constantly challenge existing dogma. 10 or even five years ago, if someone were to poll the community about whether a reaction like this could be achieved, the answer would probably be no. From working in this project, I am reminded that technological advances come from appreciating the current state-of-art/existing dogma but to always take it with a grain of salt!
A summary of the new research can be found on the Science Daily website.
