Innovation is the right word to describe our main contribution to your project. Heterocycles, PROTAC’s, macrocycles, macrolide-steroids conjugates, nucleosides, carbohydrates and peptides are just some of the chemotypes we have worked with. Target molecules are obtained using different synthetic transformations and functional group inter-conversions such as:
- Asymmetric catalysis
- Photo and Electrochemistry
- Transition metal catalysis
- Flow chemistry
- Natural product synthesis
To answer a challenge we will employ microwave assisted synthesis, resort to multistage synthesis, or just use parallel synthesis to make small to medium sized focused libraries. Let us apply modern synthetic methods and principles to synthesize your compounds by unifying hard science with scientific creativity.
Interesting and challenging chemotypes and techniques:
PROTAC’s:
PROTACs offer an efficient way to target undruggable proteins by means of biochemical degradation. For this purpose PROTACs hijack the physiological ubiquitin-proteasome system. PROTACs are molecules built from two ligands – one for the target protein to be degraded and one for the appropriate ligase – linked with a linker. They work like catalysts bringing these two proteins to close proximity thus enabling the proteolytic degradation and removal of the target protein.
Over the last several years almost ¼ of Selvita scientists have become involved in multiproject collaborations related to PROTACs. We have acquired the relevant expertise in ligase ligand identification, which is usually considered a very difficult task. We designed and synthesized the ligands, linkers and the whole PROTAC molecules. Selvita chemists have built a toolbox of various linkers (PEG, carbon chain, heterocycle etc.), potential connection points (amine, amide, ester etc.). We have worked with over 50 different warheads and 80 linkers. We also developed a range of special purification techniques for these molecules.
The PROTACs we obtained were studied by our in vitro pharmacology team using a number of biochemical and biophysical methods such as SPR and ITC. These techniques have been used to evaluate the binding of ligands to assess the binary complex formation (ligand/protein and ligand/ligase). One could also monitor the formation of the ternary complexes between the target protein, PROTAC and the ligase. The functional behavior of the PROTAC could be evaluated by the loss of the target protein and by looking at the expected functional effect.
Macrocyles:
Macrocycles belong to the “Middle” chemical space with structural and physicochemical properties positioned between small molecules and biologicals. Those molecules are very unique although most of the time macrocycles do not follow Lipinski’s rule-of-5,they do fit into the druggable physicochemical property space. The structural complexity of macrocycles results in conformational richness that determines the physicochemical and biological properties in a way that differs from the small-molecule chemical space.
Our scientist inspired by their unique properties designed, synthesized and characterized novel library FideltaMacro® based on this chemotype.
FideltaMacro® synthesis strategy:
The general synthetic strategy (Scheme 1) comprises several steps as described previously.1 Step 1 is ring opening of macrolide scaffold by oxidative cleavage of the 11,12-diol moiety to afford the seco compound B, which is suitable for further modification of secondary amino group and insertion of desired motifs, fragments, potential pharmacophores and hot spots from known protein-protein interactions (Step 2). Seco compound B still contains the 11C-13C fragment of the macrolide which serves as a protecting group for the carboxylic acid group on 1C. After deprotection of the amino group, a variety of chemical reactions can be used for insertion and further modifications of desired fragments followed by macrocyclization (Step 3). Once the macrocycle is formed, the side chain modification (Step 4) can be performed as a final step towards specific target molecules or for preparation of small focused libraries around each macrocyclic scaffold.
Scheme 1. Synthetic strategy for the preparation of FideltaMacro® compounds based on azithromycin scaffold.
About macrocycles and their uniqueness you may read more on our blog.
Isotope labelling:
Drug design is a very long and expensive process and sometimes unexpected results such as poor stability, toxicity of a metabolite or some drug-drug interaction of the drug candidate can be encountered. To prevent or at least to limit the formation of unwanted metabolites, a medicinal chemist selects the problematic parts of the molecule and applies specific substitution using bioisosteric replacement to improve the structure.
Recently, a number of studies have been performed on selective replacement of hydrogen (protium) with deuterium, naturally occurring and stable isotope of hydrogen. The increased C-D bond strength (6-10-fold) usually results in increased metabolic stability of the molecule and extended metabolic half-life of the drug.
In Selvita laboratories we develop several synthetic methods to introduce Deuterium including classical approach as well as visible-light induced deuteration of drug molecules often allowing for the late-stage deuteration of complex structures.
Beside Deuterium our chemist have experience also in introduction of carbon and nitrogen isotopes namely 13C and 15N.
About deuterium in Drug Discovery process you may read more here.
Synthesis of fluorinated molecules
Many modern small molecule drugs contain fluorine to improve their pharmacological properties. Consequently, fluorine could be found in 40% of all the drugs approved by FDA in 2019. To enable the synthesis of complex fluorinated compounds, new synthetic methods are needed. Such methods should make it possible to synthesize new, difficult to obtain fluorinated compounds having increasing level of complexity.
Selvita scientists have contributed to this area by discovering new mild fluorination protocols as well as new methods of trifluoromethylation (patent applications P.433251 and P.436698). These proprietary protocols add to the existing spectrum of fluorination methods and make it possible to expand the range of targeted structures. They also enable fine tuning the pharmacological properties of compounds thus bringing immediate benefit to drug discovery programs of our Clients.
Selvita offers some of the most advanced synthetic technologies available on the market:
- Photoredox catalysis in a batch
- Photoredox catalysis in flow
- Conversion of difluoroalkenes into difluoroalcohols, ketones and amines containing a unique structural fragment, which may help secure IP for such compounds
- Trifluoromethylation of heteroaromatic systems
The role of the fluorinated compounds can be further reviewed on our blog.