Carbohydrates play a crucial role in biological life. The synthesis of carbohydrate molecules in this work are for studying biological processes.
Uropathogenic E. coli (UPEC) is the major cause of urinary tract infections (UTIs). The ma-jority of UTIs begin in the bladder, which is the main target organ, causing cystitis or acute inflammation (pyelonephritis) in the upper part of the urinary tract as a result of the bacterial colonisation. This colonisation can be initiated via the FimH adhesin located at the tip of type 1 pili. FimH can recognise a wide range of glycoprotein mannose structures. This knowledge can support the synthesis and design of receptor mimetics. A range of inhibitors have been synthesised to block or inhibit the FimH receptor interactions.
The C-monosaccharide derivatives described in this work (Figure A) have been synthesized as probes and as novel therapeutics for investigating the binding site of the uropathogenic Escherichia coli (UPEC) in urine, the major cause of urinary tract infections (UTIs).
In more detail, this work describes the synthesis of FimH anti-adhesives which are α-C-(8-azidooctyl)-mannoside, α-D-C-(8-azidooctyl)-rhamnoside and α-L-C-(8-azidooctyl)-rhamnoside. Compound α-C-(8-azidooctyl)-mannoside is an analogue of the terminal part of uroplakin 1a (UP1a), a protein found on the superficial epithelial umbrella cells of the bladder. While the other compounds II and III are intended as reference compounds (non-binder II and weak binder III).
The syntheses start all with the introduction of the pseudo anomeric C-allyl group using known procedures from an appropriate monosaccharide as intermediate. However, a chain of 8 atoms has been proposed to be effective for good binding to FimH. Therefore, the key step for the preparation of the target compounds is connecting the remaining linker atoms includ-ing an additional functional group that will allow for further conjugation, e.g. in order to achieve multivalent analogous, to the 3-(1'-deoxyglycopyranos-1'-yl)-1-propenes. Both the Wittig reaction and the cross metathesis (CM) were evaluated for this chain extension step and the Wittig reaction was found to superior over the CM which gave inseparable side prod-ucts and thus impure target compounds. The final compounds I, II, and III were character-ized by 1H-NMR and 13C spectroscopy. In order to achieve multivalent presentation of the ligands and additional linker, 2-(2-(prop-2-ynyloxy)ethoxy)ethanthioacetate 171, was at-tached via click chemistry to theses compound. In situ removal of the thioacetate enables con-jugation to gold nanoparticles and thus multivalent conjugates.