Development of novel coumarin- and ruthenium-based photodynamic therapy anticancer agents

Résumé

Photodynamic therapy (PDT) is a clinically approved modality for the treatment of cancer. In this therapy, light is used to activate a pharmacological substance called photosensitizer (PS) and convert molecular oxygen into cytotoxic reactive oxygen species (ROS), which induce cancer cell death. The prospect of using this light-mediated anticancer strategy is attractive since it allows selective cancer targeting and low invasiveness owing to the spatial and temporal control over drug activation. However, the clinical therapeutic effect of PDT is greatly restricted by the low concentration of oxygen present in tumours (hypoxia) and the poor penetration of light into biological tissues. This Thesis explores the development of different families of chemical compounds as novel photodynamic anticancer agents aimed to address some of the major limitations of current PDT agents. The Introduction section includes an intensive revision of the state of the art in oncological PDT and in the current development of organic fluorophores, transition metal complexes and metal-organic conjugates as PSs. The Results and Discussion sections is divided into 3 chapters. The Chapter I presents a library of organic fluorophores based on COUPY coumarin derivatives and its applicability as PDT agents upon visible light irradiation. Through a systematic study, a structure–activity relationship rationale was established, which allowed the identification of three lead compounds with potent phototherapeutic anticancer activities under hypoxia and minimal toxicity toward normal cells. Acting as mitochondria-targeting compounds, their photobiological mechanisms of action were further elucidated. The Chapter II comprises the development of cyclometalated Ru(II) polypyridyl complexes of the formula [Ru(C^N)(N^N)2]+ as biologically-compatible green light photosensitizers with high phototherapeutic efficacy under hypoxia in cancer cells under short times of irradiation. Finally, the Chapter III of this manuscript addresses the development of a novel hypoxia-active PS based on the conjugation of a cyclometalated Ru(II) polypyridyl complex to a near infrared (NIR) NIR emitting COUPY coumarin. Spectroscopic and photobiological studies revealed that this metal-organic conjugate exhibits high photoactivity toward cancer cells after highly penetrating NIR light irradiation under hypoxia, which could circumvent tissue penetration issues and alleviate the hypoxia limitation of PDT. Overall, this research work sets the stage for the development of novel coumarin and ruthenium based photodynamic anticancer agents and paves the way to the obtention of highly potent, NIR- and hypoxia active PSs with advantageous chemical and biological properties. In conclusion, this Thesis contributes to the development of novel classes of organic and inorganic compounds as anticancer tools in PDT.