Towards the synthesis of a macrocyclic E-selectin antagonist

Towards the Synthesis of a Macrocyclic E-selectin Antagonis:
Introduction:
Selectins are involved in the orderly migration of leukocytes from blood vessels to sites
of inflammation. Although extravasation of leukocytes represents an essential defense
mechanism against infection, excessive or inappropriate leukocyte accumulation results
in injury to host tissues. Therefore, the development of selectin-antagonists is
considered as an effective therapeutic approach in inflammatory and other disorders.
Physiological selectin ligands contain a common tetrasaccharide epitope called sialyl
LewisX (1) that has served as the lead structure in our rational design of E-selectin
antagonists.
Purpose:
The sLeX analog 2 was rationally designed to explore the role of the spatial orientation of
the pharmacophores in the conformation bound to the receptor. The rigidity of the
macrocyclic core should provide the basis for enhanced bioactivity due to preorganization
of the functional groups involved in binding in the bioactive conformation.
The building blocks for the synthesis of 2 are L-galactose, elongated at C-6 by Wittig
olefination, D-talose alkylated at the 3-OH with (S)-cyclohexyl lactic acid and an acyclic
replacement of D-GlcNAc. Activity studies of the 2 will provide an important contribution
to the validation of our predictions based on pre-organization determined by molecular
modeling.
Results:
The building blocks required by the retrosynthetis of target molecule 2 were synthesized
in good to excellent yields. The core structures 79 and 91b were obtained as the results
of two different synthetic pathways.
The targeted macrocycle could not be synthesized due to major synthetic hurdles that
have been encountered along the two respective pathways.