top of page

DC6: MARC SAN JOSÉ GRACIA (SP)

Partner of attachment: SANOFI (Sanofi GmbH) DE

 

Supervisor: Dr. Anna SIB

 

University of Attachment: IQS (University Ramon Llull) SP

 

Director of Thesis : Prof. Ana Belén CUENCA GONZALÉZ

Marc San José GRACIA IMG_20210913_093152_edited.jpg

Isotope chemistry has a direct application in pre-clinical and clinical phases of new-come pharmaceuticals. ADME studies to assess the metabolic safety profile, unveil drug metabolism, disposition, and PKs of novel Lead Candidates will be conducted from drugs bearing long-lived radionuclides. Resulting from a range of isotopes, carbon-14 (14C) allows to recruit this critical information based on the fate of synthetic organic molecules in the body. The extensive attention in tracking molecules within living systems that rely on this isotope is well supported by the properties of its radioactive atom: 1) long half-life (5730 ys), 2) low E β-particle radiation, and 3) high stability in biologicals fluids.

 

As a consequence of their relevance for pharmaceutical and agrochemical industries, the development of an efficient and late-stage labeling methodology sits at the core of our research field. Unlike the stable and naturally abundant 12C, the synthesis of organic frameworks with isotopeC requires careful optimization to overcome radiochemical challenges including high cost of starting materials, harsh conditions, and the generation of radioactive waste. Aligned to this purpose, Carbon Isotope Exchange (CIE) emerged in the last 5 years as a fast, clean and cheap strategy. Despite the many advantages that this method presents, there are still challenges in accessing biological compounds due to the increased complexitiy and intereferences of these molecules.

 

The main feature of our project lies on devising an innovative approach to label nucleotides in a late-stage approach. Derived from a huge variety of chemical structures that can be found in multiple marketed drugs, these N-containing molecules constitute the basic building blocks of nucleic acids, which in turn play a crucial role in protein synthesis via base pairing and are part of the reason of our existance through genetic encoding. Nucleobases represent the small molecules conformed by purines and pyrimidines upon which labelling exchange could be achieved.

 

Purines are relatively stable heterocycle systems containing a fused pyrimidine and imidazole ring, and are recognized as priviledged molecular scaffolds in medicinal chemistry to synthesize effective therapeutic agents. The synthetic strategy carried out conveys the study of a suitable method to substitute the “exogenous” carbon isotope by the natural carbon-12 via an efficient atom exchange. For this achievement 4 bonds precise to be broken and formed again. In the field of chemical research and methodology, addressing this opportunity suppose a gigantic challenge.

 

The source providing the radioactive label 14C isis carbon dioxide (14CO2) which is generated from a primary Ba[14C]CO3 building block. Nonetheless, the catalytic conversion of this non-toxic, cost efficient and abundant raw material, into small and useful molecules is one of the main challenges mainly due to its high thermodynamic stability.

 

In light of the aforementioned, our purpose is to develop a CIE reaction based on a reductive CO2 activation with high radiochemical yield on nucleobases that can later be translated to nucleotides and bigger in size biological – based compounds such as RNA/DNA chains.

 

Enchanted by the scope of this challenge, we needed to establish a strategy that ensured the incorporation of the external carbon-isotope (*C) and substitution of the 12C already present in the initial purine substrate. Since the radiochemical waste that can be produced is limited to low amounts of 14C-derivatives, we are currently studying this system with another non-radioactive carbon isotope (13C). First results indicate the incorporation of 13C in the desired nucleobase in a 1:1 12C/13C ratio.

 

Based on the model nucleoside compound used for the initial study of this project, we can conclude that the major challenge in this system is to find suitable conditions for an efficient carbon isotope exchange (CIE) reaction amenable to ensure specificity to the position aimed to introduce the label.

Capture d’écran (198).png
bottom of page