Scalable Synthesis of 17S-FD-895 – An Interview

The magazine Cell Reports Physical Science recently published an article involving several of our colleagues, called 'Scalable Synthesis of 17S-FD-895 Expands the Structural Understanding of Splice Modulatory Activity'. Two of our scientists involved in this project, Dominika Bachera and Martijn Slagt, answered some questions for you.

Dominika: My name is Dominika Bachera and I’m from Poland. I hold a PhD in synthetic organic chemistry. I started working at Symeres (then: Syncom) eight years ago, right after my PhD studies. I’m a project leader in the Medicinal Chemistry Department at Symeres.

Martijn: I am Martijn Slagt and I did my Master’s and PhD at Utrecht University in organometallic chemistry. I have been working at Symeres since 2017 and previously at Syncom between 2003 and 2011. Between 2011 and 2017, I worked in product development at Henkel Adhesives. I’m a senior scientist in the Medicinal Chemistry team.

Martijn: The University of California San Diego (UCSD) was working on the development of a scalable total synthesis of a natural product derived splice modulator, 17S-FD-895. This is a therapeutic lead in the treatment of malignancies (leukemia, solid tumors) characterized by splicing deregulation.

Dominika: The goal of this research was the scalable synthesis of 17S-FD-895 that would provide gram quantities of the drug, which were required by the client to complete preclinical evaluation.

Martijn: Symeres provided support in both scale-up and method optimization for the production of the key building blocks.

Dominika: 17S-FD-895 is a complex molecule, consisting of a macrolactone that is connected to a side chain by a diene. Its synthesis requires multiple steps, with some challenging chemistry along the way. With 11 stereocenters in total, high stereoselectivity of reactions was pivotal and, in some cases, needed to be enhanced. To develop a scalable process, not only optimization of the reaction conditions was required, but also improvement of purifications, or ideally, their number reduced.

Martijn: We looked for improvements in the enantio-/diastereoselectivity of the synthetic steps for the production of the building blocks. The production of the final product needed to be performed in a restricted amount of time, including the final step at the containment lab to produce the highly potent product.

Dominika: For that final step, Martijn had to wear appropriate personal protective equipment to ensure utmost safety and security.

Martijn: I am proud of performing the full synthesis of the highly potent final product within the set timelines and thereby enabling the client to fulfil their requirements for future funding of their project.

Dominika: The fruitful collaborative effort between UCSD and Symeres on this project was concluded with the publication of an article titled ‘Scalable Synthesis of 17S-FD-895 Expands the Structural Understanding of Splice Modulatory Activity’ in Cell Reports Physical Science in December 2020. It was nice to see that the whole team’s work was recognized in this way.

 
 

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