Innovative approaches for targeted therapy and sustainable processes for API synthesis

Targeted therapy is a promising strategy for the treatment of numerous diseases aiming to reduce off-target effects and enhance efficacy of drugs. In this context, the design of Antibody-Drug Conjugates (ADCs), in which cytotoxic payloads are conjugated to monoclonal antibodies through a linker, appears to be a remarkable approach to promote the selective activation of the drug in the target tissues. With this goal in mind, ongoing research is focussed on the development of new linkers based on specific release systems and the selection of promising new drugs to bind to antibodies. In this thesis, the development of unconventional ADCs will be discussed. An unconventional cathepsin-sensitive linker was designed to develop the first ADC based on ProTide technology with the aim of overcoming the critical issues, such as toxicity and resistance, associated with the administration of nucleoside analogues and other phosphorylated drugs. In addition, ADC technology was exploited to mitigate the toxicity associated with a dual ERK-5 and ERK-1 inhibitor. This drug was conjugated to monoclonal antibodies using both a non-cleavable and a cleavable linker. The cleavable linker, designed to release the drug under acid conditions, was also employed to the synthesis of pH-responsive prodrugs of amide-containing active pharmaceutical ingredients. Moreover, given the growing relevance of immunotherapy in cancer treatment, a novel class of small molecule inhibitors targeting the PD-1/PD-L1 signalling pathway has also been developed. An original 1,4-benzodiazepinone scaffold was functionalised accordingly with the key elements identified by SAR (Structure-Activity Relationship) studies. Finally, an environmentally friendly process for the synthesis of indoles, important building blocks of several active compounds, was developed starting from differently substituted 2-alkynylalanine.