Towards palladium-catalysed in cellulo synthesis of anticancer drugs

Details

Supervisors

Riant, Olivier

Faculty

Faculté des bioingénieurs

Degree label

Master [120] : bioingénieur en chimie et bioindustries, à finalité spécialisée

Abstract

Cancer, the second leading cause of mortality worldwide, remains a significant challenge in modern medicine. This disease is characterised by altered metabolic profiles in malignant cells. Targeting these metabolic vulnerabilities offers a promising strategy for anticancer therapy. The lactate metabolism, a key component of cancer cell metabolism, has gained considerable attention in this regard. This research aims to develop a new method for the synthesis of anticancer drugs using a palladium-catalysed Tsuji-Trost reaction directly at the tumour site. This strategy exploits the unique metabolic vulnerabilities of cancer cells, specifically the expression and activity of the mitochondrial pyruvate carrier (MPC), to selectively deliver potent anticancer agents directly to cancer cells. The research objectives include the design, synthesis, and selection of optimal prodrug candidates, the optimisation of the Pd-catalysed reaction in biological media, and the evaluation of drug delivery under biological conditions. Three prodrug candidates (P1, P2, and P3) were designed and synthesised, with P3 identified as the most suitable candidate based on reaction kinetics, yield, and selectivity. Optimal conditions for the Pd-catalysed reaction were established, and the impact of reaction media was studied. The presence or absence of serum did not alter the reaction outcome, giving approximately the same conversion rate. Biological assays revealed that the prodrug was unable to penetrate cells, a factor which did not impede the intended outcome of the reaction. These assays also demonstrated improved cytotoxicity results for the reaction after 72 hours, with specific palladium catalysts. However, 7ACC did not exhibit the expected cytotoxicity, suggesting that further investigation is necessary. In conclusion, the successful release of the drug at the tumour site resulted in the death of SiHa cancer cells, leaving less than 10% cell viability after 72 hours of treatment. This outcome was achieved by exploiting the unique metabolic vulnerabilities of cancer cells. This study highlights the potential of Pd-catalysed reactions in drug synthesis and provides insights for future anticancer treatment development.