Chapter 2 describes the preparation of the building blocks and the optimisation of the solid phase synthesis of hairpin polyamides containing Nt units. Chapter 1 introduces the endogenous and exogenous DNA recognition by protein and small molecules, the modulation of gene expression using Py-Im polyamides and the limitations of this approach.
This thesis describes the preparation and the evaluation of the binding mode of hairpin polyamides with Im units replaced by a series of 5-substituted 2-amino-4-carboxylic thiazole(Nt) building blocks. Although modifications to the periphery of the polyamide scaffold have been explored at length, there has been limited studies on tuning the physicochemical properties of the G-recognising Imunit. Im-richpolyamides tend to have reduced cellular and nuclear uptake in eukaryotic cells. A current limitation of the biological applications of Py-Im polyamides is their variable cell permeability profile. The possibility to target specific dsDNA sequences enables polyamides to modulate gene expression by the disruption of transcription factors such as the androgen receptor, over expressed in prostate cancer. An Im-Py pair discriminates G over C, A and T, whereas a Py-Pypair binds A and T over C and G. The hairpin conformationenables sufficient flexibility to form a side-by-side arrangement within the minor groove of target dsDNA sequences. Pyrrole-Imidazole (Py-Im) hairpin polyamides are a programmable class of compounds that bind in the minor groove of double-stranded DNA (dsDNA).Department of Pure and Applied Chemistry.