Rationally designed aplyronine analogues for use in antibody-drug conjugates
The aplyronines are a family of antimitotic marine macrolides which show highly potent antiproliferative effects at picomolar concentrations in human cancer cell lines. Through a novel dual protein-targeting mechanism of action, their exquisite potency renders the aplyronines promising drug candidates. However, the scarcity and structural complexity of the aplyronines brings challenges in supplying material to enable these studies, and calls into question their viability as commercial targets. Based on structure–activity relationship studies for the aplyronines and some related actin-binding macrolides, we have designed simplified analogues with the aim of reducing the synthetic effort, whilst retaining the extraordinary potency of the natural products. Our highly convergent route has led to a substantial reduction in the step count and improved scalability. Importantly, recent advances in cancer chemotherapy have led us to consider conjugating the aplyronines to monoclonal antibodies to produce improved antibody–drug conjugates to target specific tumour cells. Chapter 1 places this project in the context of marine natural products research for applications in the clinic. Background is given on the extensive work previously undertaken on the aplyronines in our group and others. Based on this, the rational design of analogues is justified and a plan is laid out for their efficient synthesis. The field of targeted cancer therapy is introduced, with particular reference to the antibody–drug conjugate approach. Chapter 2 discusses the methods used to construct key fragments for these designed aplyronine analogues. The southern fragment contains two of three key structural simplifications, while the side chain contains the final modification. Details are also given for the re-synthesis of the northern fragment, originally devised for the natural product, to supply this research. Chapter 3 recounts how these fragments were combined and elaborated to a highly advanced intermediate. We examine the selection of an optimal protecting group strategy for the northern region from two options, leading to the scaled-up synthesis of a fully protected macrocylic compound. Finally, attachment of the modified side chain provides the full carbon skeleton. Chapter 4 culminates in endgame manipulations to furnish the desired analogues, and explores the potential of these compounds to be advanced to the clinic for cancer therapy. Strategies for conjugation to antibodies to develop a targeted therapy are considered, along with prospects for further streamlining of structure and methodology leading to a new generation of analogues. Chapter 5 provides experimental details of the work described in this thesis, along with full analytical data for compound characterisation. Further supporting information, including copies of NMR spectra for key compounds, is given in the appendices.
aplyronines, total synthesis, antibody-drug conjugates, targeted therapy, rational design, function-oriented synthesis, polyketides, stereoselective synthesis, analogues, organic synthesis, aldol reaction, aplysia kurodai, natural products, anticancer, cancer therapy
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