Synthesis and biological evaluation of prodrugs activated by reactive oxygen species from the tumor environment
Cancer is one of the leading cause of death worldwide, accounting for 15 million deaths per year. The drugs available in clinic often present similar toxicity towards both cancer and normal cells. Therefore, there is an urgent requirement for alternative chemotherapies. A relevant strategy relies on the development of prodrugs, masked forms of active drugs that are designed to be activated after an enzymatic or a chemical reaction. In this project, prodrugs are prepared for the specific activation by the tumor environment. A targeting moiety is added to the prodrugs in order to increase the molecular uptake into cancer cells.
Ecodesign of Drugs contaIning a selF-Immolative Scaffold (EDIFIS)
For many years, drugs and their metabolites have been subject to unrestricted emissions to the environment. The detection of an increasing number of pharmaceuticals in drinking water, coupled with their persistence in the environment, led to consider the environmental impact of a drug’s entire life cycle. In this context, the EDIFIS project focus on the development of a methodology for the ecodesign of drugs. The principle of our strategy is based on the programmed inactivation of drugs. Once entered the environment as waste, “ecodrugs” will undergo particular modification in the biomass, which will trigger the self-disassembly of the latter with loss of original activity. In our strategy, the sensitive moiety is a self-immolative scaffold as self-immolation processes are particularly well-studied. The drugs containing the latter scaffold will be deactivated by predictable metabolism either by hydrolytic or oxidative processes. Since 75% of the APIs on the market are not biodegradable, the first objective of this project is to redesign the most problematic drugs. The self-immolative moiety must be located within the molecule in such manner that the overall physicochemical, steric and complementary properties of the “ecodrugs” are very close to the lead compound.
A chemically-encoded timer for dual molecular delivery at tailored ranges and concentrations. S. Serra, A. Alouane, T. Le Saux, S. Huvelle, A. Alouane, R. Plasson, F. Schmidt, R. Labruère, Chem. Commun., 2018, 54, 6396-6399
Synthesis and antikinetoplastid evaluation of bis(benzyl)spermidine derivatives. E. Jagu, S. Pomel, A. Diez-Martinez, E. Rascol, S. Pethe, P. M. Loiseau, R. Labruère, Eur. J. Med. Chem., 2018, 150, 655-666
Polyamine-based analogs and conjugates as antikinetoplastid agents. E. Jagu, S. Pomel, S. Pethe, P. M. Loiseau, R. Labruère, Eur. J. Med. Chem., 2017, 139, 982-1015
Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates. E. Jagu, S. Pomel, A. Diez-Martinez, F. Ramiandrasoa, R. Luise Krauth-Siegel, S. Pethe, C. Blonski, R. Labruère, P. M. Loiseau, Bioorg. Med. Chem., 2017, 25, 84-90
Self-Immolative Spacers: Kinetic Aspects, Structure–Property Relationships, and Applications. A. Alouane, R. Labruère, T. Le Saux, F. Schmidt, L. Jullien, Angew. Chem. Intern. Ed., 2015, 54, 7492-7509
Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives. E. Jagu, R. Djilali, S. Pomel, F. Ramiandrasoa, S. Pethe, R. Labruère, P. M. Loiseau, C. Blonski, Bioorg. Med. Chem. Lett., 2015, 25, 207-209