Cancer is the second most fatal disease. The treatment opportunities have been improved quite a lot in the last decades, but the efficient cure of some tumors with high mortality is still a challenge. Targeted tumor therapy might provide a breakthrough on this area in the future. This technique is based on conjugates in which anticancer agents are linked to small molecules like peptides that recognize selectively the tumor cells. The biggest challenge during the development of such types of conjugates is the finding appropriate linkers that provide high stability in the circulation but allow efficient release of the free drug or its active metabolite in cancer cells. In some cases the size of an appropriate linker that allows the release of the free drug can prevent the binding of the small peptide to its receptor on tumor surface. On the other hand, different metabolites might be localized in different compartments in the cells resulting in different activity. Therefore, different linkage systems should be compared for the development of appropriate conjugates for targeted tumor therapy.

In our research, efficient anticancer drugs that were previously prepared in our laboratory will be modified by different functional groups that provide conjugation sites for complementary functional groups on homing peptides developed mainly for cancer type with high mortality. For this purpose, functionalities allowing the formation of amide, ester, oxime, disulfide and tioether linkages will be introduced into the drug molecules. Besides the appropriately selected self-immolative linkers 1,4- or 1,5-disubstituted [1,2,3]triazoles will also be implemented in the conjugates by means of metal catalyzed regioselective azide-alkine click reactions.

To optimize the bioactivity and bioavailability of the conjugates, different functional groups in different positions of drug molecules will be investigated to enable various metabolic pathways.
Complementary functional groups (e.g. amine, carboxyl, thiol, aminooxy, azide, chloroactyl, alkine) will be incorporated to homing peptides developed for tumor types causing high mortality.

Gábor Mező, Antal Csámpai

Result_May 2020