This report describes two projects. The first focuses on the synthesis of a library of small molecules suitable for fragment-based screening. Over the past two decades, fragment-based drug discovery (FBDD) has emerged as a powerful strategy for early-stage drug discovery. However, despite its many successes, FBDD often suffers from the lack of synthetic tractability, three-dimensionality, and structural diversity (and hence biological diversity) within traditional fragment collections. As such, there is a need for the generation of novel fragment collections with these features to augment existing collections.

This work documents the diversity-oriented synthesis of a library of 38 diverse and sp3-rich fragments, each bearing a key all-carbon quaternary centre. These motifs are currently underrepresented in screening collections; thus, it was expected that the incorporation of such a moiety would enable access to new areas of fragment space, whilst enhancing three-dimensionality. Each fragment was prepared in no more than four steps, providing a facile route by which fragments containing an all-carbon quaternary centre and multiple fragment growth positions could be generated. Importantly, the resulting library adheres to recognised guidelines within the field of FBDD, thereby demonstrating its suitability as a screening collection.

The second project details the development of a platform for the site-selective dual modification of antibodies via a cysteine rebridging strategy. The site-selective modification of antibodies for use in both drug delivery and immunodetection has gained widespread interest in recent years, particularly in the field of oncology. Although many strategies have been developed to enable such modifications, the majority only enable the incorporation of a single type of payload, thus limiting their scope. Furthermore, of the methods for the dual modification of antibodies that have been developed, many suffer from several drawbacks, including lack of efficient conjugation methods, problems with stability and solubility, incomplete conversions, low yields, and/or the use of toxic metal catalysts.

To tackle these issues, the disulfide rebridging reagent divinylpyrimidine (DVP) was modified to incorporate two orthogonal ‘clickable’ handles. By the introduction of the DVP linker into the native disulfide bonds of an antibody, subsequent one-pot dual functionalisation was successfully demonstrated to attach both cytotoxins and fluorophores. Notably, this strategy enabled the generation of theranostic antibody conjugates that exhibited selective in vitro cytotoxicity.