Synthetic Strategies Towards Substituted Purines and Their CSF1R Activity

Abstract

Overexpression of colony stimulating factor 1 (CF1R) has been implicated in a number of disease states, such as cancer, inflammatory disorders and bone disease. Inhibition of the colony stimulating factor 1 receptor kinase (CSF1R) is an emerging target in the search for treatments for these pathological conditions.

The aim of this master thesis was to investigate synthetic routes towards 6-amino-8-aryl-purines and explore their inhibitory potency towards CSF1R. One synthetic route was investigated using three different protecting groups (THP, benzyl, PMB). Introduction of a protecting group at N9 and halogenation at C8 in 6-chloropurine provided a highly useful building block for further functionalization. Subsequent amination and Suzuki cross-coupling reactions yielded the N-protected 6-amino-8-arylpurines. Finally, deprotection of the THP-protected 6-amino-8-arylpurines gave the target 6-amino-8-arylpurines.

The THP-protected building block was synthesised during the pre-master project. However, the yields were low due to challenges encountered in the work up and purification processes. In an attempt to achieve an easier introduction of iodine in the halogenation step, two additional protecting groups were used in this thesis. Halogenation using the benzyl-protected 6-chloropurine gave yields in the range 77-95%. Both amination at C6 and Suzuki cross-coupling at C8 proceed with ease with the N9 benzyl protecting groups.

In vitro enzymatic assays were conducted for compound 17 and 18. Single-point analyses and measured IC50-values of compound 17 (IC50=1.3 nM) revealed a remarkable activity towards CSF1R. In contrast, compound 18 was inactive. In silico docking experiments indicated that the increased activity is caused by hydrogen bonding between the ortho-hydroxymethyl group and Leu588.