“I believe that at the start of any research, you cannot be certain that you will solve a significant global problem,” says Dr Toms Kalniņš, a doctor of chemistry and an assistant at the LIOS Laboratory of Advanced Technologies in Organic Synthesis, who defended his doctoral dissertation at the end of last year. “However, immense motivation, a solid foundation of knowledge, and an unwavering determination to explore every possible avenue are essential to success.”
“When embarking on research, you step into the unknown, as you need to forge new paths different from those taken by others before you to achieve results that have not yet been attained,” says the young scientist. His doctoral thesis explored ways to make diazonamide A – a natural compound found in marine sponges – more accessible for the development of new anti-cancer drugs. Toms sought methods to synthesise this compound in laboratory conditions and worked with similar compounds previously developed by scientists worldwide, striving to make them more active, stable, and suitable for practical applications and the development of new drugs. His dissertation was titled “Studies on the Synthesis of Diazonamide A and its Structural Analogues.”
For the past few years, Dr Kalniņš has been focusing on a different field of research – the development of antibacterial compounds free from resistance. Nevertheless, over the past year, alongside his main work, he dedicated time to transforming his many years of scientific effort into a doctoral dissertation.
Synthesising Nature’s Complexity
Toms first encountered the idea of synthesising a molecularly complex natural compound in the laboratory and investigating which parts of it were responsible for its anti-cancer properties 12 years ago in Professor Edgars Sūna’s laboratory. This research also provided him with an opportunity to intern at the University of Michigan under Professor Edwīns Vedējs, whose long-standing scientific interest was related to the synthesis of diazonamide A.
“The research into the total synthesis of diazonamide A became the first and most exciting phase of my doctoral work,” Toms recalls. “Total synthesis in chemistry is like embarking on a real adventure. It allows you to use everything developed in methodology so far. Your brain is constantly working because you have to come up with new solutions to the obstacles that continuously arise. Sometimes, you may have to design 1,000 reactions just to overcome a single step. And each reaction has to be thought out individually. It was truly fascinating,” he says.
However, like his international colleagues (who had published four successful total syntheses), Toms encountered the same issue they had faced. Synthesising the compound – whether from natural materials or through synthetic means – proved to be a highly time-consuming and complex process, one that did not always lead to success.
Searching for Active Compounds
As his research progressed, Toms decided to change his approach in the search for new drugs. He explored modifications to a simplified analogue of diazonamide A, developed by Professor Patrick G. Harran, with the aim of making it more stable and active. This approach held the potential to develop new anti-cancer drugs faster and at a lower cost while also offering insights into the relationship between compound structures and their activity. During this phase, Toms created three new, previously unreported macrocyclic compounds and concluded that changes to the central structure of the molecule were not permissible. In the third phase of his work, he explored the possibility of creating even simpler analogues of diazonamide A by replacing the compound’s complex core with a significantly simpler structure.
“Along the way, countless inactive compounds were produced, but by focusing on one particular motif, we managed to achieve an activity level that colleagues could continue to optimise,” says Toms. Using the developed synthesis method, Toms created diazonamide A analogues that demonstrated good anti-cancer activity against several cell lines. “his enabled my colleague Viktorija Vitkovska, an assistant at the OSI Laboratory of Advanced Technologies in Organic Synthesis and a doctor of science, to study how these compounds interact with enzymes and cells,” Toms explains.
A Modest Contribution to Global Knowledge
Asked how he reflects on the process of completing and writing his dissertation, Toms admits that, with several interruptions and involvement in other projects, it took him 11 years. “Together with my supervisor, Professor Edgars Sūna, we concluded at the start of last year that the work needed to be consolidated, written up, and brought to a logical conclusion,” says Toms.
Reflecting on his confidence and initial ambitions at the start of his journey, Toms admits with a smile – and even some frustration – that it is human nature to significantly overestimate oneself and one’s knowledge, especially in youth.
“Looking back, my unshakable confidence in my knowledge seems both naïve and comical, but it’s enlightening to view one’s work through the lens of time,” he says.
“Beyond the support of my family and my supervisor, creating a doctoral dissertation is a real test for oneself,” Dr Kalniņš acknowledges. “The difficult phases are compensated by small successes and a sense of mission – that you are doing this for the benefit of humanity, as there is a growing need for effective anti-cancer drugs in the world. Moreover, drugs that are less toxic or have comparatively lower toxicity.”
Looking Back on a Decade of Research
“I understand that my doctoral dissertation is just a small dot in the vast landscape of global knowledge. Yet, even the smallest contributions can help expand humanity’s collective understanding,” says Toms.