Design and synthesis of MNK inhibitors for treatment of cancer

Author

Arias Donaire, Ana 

Abstract

The main cause of failure of cancer therapies is due to the resistance that cells develop against these therapies. For these resistances to take place, cells activate response pathways against stress, these are mechanisms that tumor cells use to avoid immune surveillance as well as growth inhibitory signals. One of the key events in the adaptation of these stresses is the post-transcriptional alteration in the protein synthesis pathways that would favor the expression of key genes necessary for the stress resistance phenotype. The eukaryotic translation initiation factor 4E (eIF4E) is a none-dependent protein translation factor. It is regulated by phosphorylation in Ser 209 by MNK1 / 2, this phosphorylation is necessary for oncological transformation, but not for normal cell development. This therefore makes MNK1 / 2 inhibition a good target for cancer therapies.
Previously, the group was synthesized and EB1 tester, it showed activity against MNKs. When a family was made from compost, the yields varied depending on the nature (donor or acceptor) of the group that was present. For this reason, in this master's thesis, different strategies have been proposed to solve this problem.
The first proposed strategy consists of the synthesis of a common intermediate that allows Suzuki reactions to be carried out to achieve the different molecules without the effects caused by the different groups in the previously used route. Since this was not possible, a different strategy has been proposed.
The second strategy consists of improving the first route that was used. The main problem that this one had was the synthesis of chalcones, the first stage of the synthesis. A different reaction has been tried for the synthesis of these molecules with an acceptor group and a donor to ensure the success of the reaction regardless of which group is present. The Wittig reaction has turned out to be the perfect option, allowing the synthesis of the three molecules that have been tested with good purity and good yield in all cases.

Director

Borrell Bilbao, José Ignacio
Estrada Tejedor, Roger

Degree

IQS SE - Master’s Degree in Pharmaceutical Chemistry

Date

2021-07-08