Year

2017

Degree Name

Doctor of Philosophy

Department

School of Chemistry

Abstract

Novel strategies and therapeutics for treating haematological malignancies and lowering disease recurrence are highly sought after. A promising approach towards reducing recurrence is to block the VLA-4/VCAM-1 protein-protein interaction using VLA-4 antagonists which mobilise malignant early haemopoietic stem and progenitor cells (HSPCs) from the bone marrow into peripheral blood. These cells show reduced susceptibility to chemotherapy drugs whilst in the bone marrow; an effect known as environment- mediated drug resistance. It has been proposed that mobilisation of these cells would make them more vulnerable to chemotherapy allowing them to be better cleared from the body during treatment. (±)-Thioridazine, a discontinued anti-psychotic drug, shows several useful activities against haematological malignancies, including the ability to act as a VLA-4 allosteric antagonist and HSPC mobiliser, as well as being able to selectively induce apoptosis and differentiation in malignant HSPCs. A thioridazine-VLA-4 antagonist hybrid could provide multi-action synergy in treating haematological malignancies and lowering disease recurrence. Part I of the thesis describes the design and synthesis of two epimeric hybrids.

An adaptation of the Ullmann reaction was used as the key step to produce a novel azido-VLA-4 antagonist obtained in 34% yield over 6 steps. The resolution and synthesis of northioridazine enantiomers from (±)-thioridazine was achieved, with the absolute stereochemistry confirmed by X-ray crystallographic analysis of a N-nosyl thioridazine derivative. N-Substitution of the (R)- and (S)-northioridazine enantiomers was optimised to produce the corresponding (R)- and (S)-N-propargyl northioridazine enantiomers in 22% and 21% over 4 steps, respectively. A convergent synthesis of the (R)- and (S)-hybrid epimers was achieved via a ‘click’ reaction with an overall yield of 39% and 38% over 11 steps, respectively. These molecules may serve as pharmacological tools to probe the allosteric and competitive binding pockets of VLA-4.

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