Derivatising Carbohydrates for Biological Applications
Doctoral thesis, 2005
Carbohydrates have a wide variety of functions in Nature. The somewhat old view of carbohydrates only functioning as building blocks or energy sources, has been overturned by the newer insight that carbohydrates are deeply involved in recognition processes, such as receptors for bacteria, viruses, antibodies and proteins. A good example of the latter is the beta-D-galactose recognising family, the galectins. The biological rules of this family, with its fourteen members, are not yet fully elucidated but there is ample evidence that they affect cancer and tumor progression, regulation of the cell cycle and are involved in the immunosystem, e.g. recognition and killing of bacteria. It has also been proven that galectins are associated with myocardial infarction, parasite infection and allergic inflammation. To study these types of interactions and mechanisms we need tools. Two such tools are synthetic glycoconjugates and derivatised carbohydrates.
In this thesis we have developed a mild and effective methodology for neoglycoconjugate synthesis, utilising hydrophobic didecyl squaric ester. The generality of this methodology was proven in synthesis of various neoglycoconjugates as well as a trimeric globotetraose derivative.
The sequence of formation and subsequent reaction of a cobalt hexacarbonyl complexed propargylic cation, is known as the Nicholas reaction. This reaction has been studied and used as a methodology for synthesising novel galectin inhibititors in solid phase. The method was proven to be both straightforward and flexible and the solid phase approach simplified the purification procedure significantly. The synthesised inhibitors were tested against galectin-1, -2, -3, -7, -8N and -9N. Their affinitiy ranged from poor to good.
By using a cationic dienyl iron carbonyl complex in conjunction with either acetylated methyl beta-D-galactopyranoside or a preformed stannylene acetal, alkylations were proven to be effective. In the case of the acetylated methyl beta-D-galactopyranoside, the resulting diene could be aromatised. Work is in progress to aromatise the selectively unprotected methyl-beta-D-galactopyranoside.