ChemoBOOM · Development of Palladium-Labile Prodrugs for Bioorthogonally-Activated Chemotherapy

Development of Palladium-Labile Prodrugs for Bioorthogonally-Activated Chemotherapy

The social and economic relevance of cancer in Europe is continuously growing. Despite relevant advances in early diagnosis and treatment, the highest therapeutic challenges yet resides on treating cancer patients diagnosed with late-stage cancer due to the dose-limiting adverse effects. In this context, based on the biocompatibility and catalytic activity of Pd-functionalized devices in vivo, the ChemoBOOM project was focused on the development of biochemically-stable prodrugs (i.e. bioorthogonal prodrugs) that are specifically activated by bioorthogonal heterogeneous catalysis in order to reduce systemic side effects associated of chemotherapy. The research program was divided into two specific research objectives: Objective 1: Development of novel O-Propargylated Pd-labile prodrugs of cytotoxic agents. In recent years several transition metal-mediated bioorthogonal deprotection reactions have been reported, however they can be grouped in 2 classes: the deprotection of carbamate-masked primary amino groups and the N-depropargylation of endocyclic nitrogen atoms with lactam-lactim tautomerism. As the cytotoxicity of many therapeutic agents is modulated by other chemical functionalities, the 1st specific objective of the project was to extend the scope of functional groups amenable to activation by Pd chemistry in order to increase the diversity of bioorthogonally-activated prodrugs. This is, for example, the case of hydroxamic acid-based drugs such as HDAC inhibitor vorinostat whose pharmacological activity is endowed by the metal-chelating capacity of the hydroxamic acid group. During the course of this project, we have developed a novel strategy that enabled -for the first time- to devise a completely inactive precursor of vorinostat that is rapidly uncaged by biocompatible Pd-resins in cell culture models of glioma and lung cancer. To expand the scope of the locally-controlled bioorthogonal organometallic chemistry in biomedicine, we successfully extended this strategy beyond Pd and demonstrated the bioorthogonal activation of this prodrug by a heterogenous Au catalysts. Objective 2. Development of precursors of combination therapy activated by Pd chemistry. One of the most promising approaches to address cancer heterogeneity is the use of combination therapy, which is based on the simultaneous use of drugs with different mode of actions and synergistic effect. Accordingly, the 2nd research objective of the project was to create an unprecedented class of bioorthogonal prodrug that consists in 2 chemotherapeutic drugs connected by a Pd-labile bioorthogonal promoiety that upon Pd-mediated cleavage release the active forms of each drug. Based on the uncaging chemistry validated in objective 1, we developed a novel anticancer codrug that combined 2 approved drugs into a single molecular entity and we have proved its in vitro activation via Pd-functionalized resins.

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