Synthesis and biological evaluation of carbohydrate-mimetics as ligands for Siglecs

Sialic acid binding immunoglobulin-like lectins (Siglecs) play an important role in the mediation of cell-cell interactions as well as in the regulation of signaling pathways. They are mainly expressed in the haematopoietic and immune system, with exception of Siglec-4, also called myelin-associated glycoprotein (MAG). It was identified as one of neurite outgrowth inhibitors, playing a crucial role in paraplegia, which is caused by injuries of the central nervous system (CNS) and especially young people suffer from these severe consequences as, for example, the loss of motor functions. The lack of repair of the injured nerve strands originates from the inhibitory environment for axon regeneration in the CNS. SpeciÞc inhibitory proteins, such as MAG block the regrowth of nerve roots. We identiÞed potent small molecule MAG antagonists modifies in the 2- and 5-position. Furthermore, we investigated new neuraminic acid derivatives modiÞed in the 4-position, and the inßuence of various structural modiÞcations on their kinetic and thermodynamic binding properties. In a next step we presented high affinity ligands, which were identified in second-site screenings and optimized them according to medicinal chemistry aspects. All ligands were elucidated with respect to their binding affinity as well as their kinetic and thermodynamic profile. Siglec-2, also known as CD22, is involved in the regulation and survival of B-cells and has been successfully targeted in cell depletion therapies with antibody-based approaches. Sialic acid derivatives, already known to bind with high affinity to myelin-associated glycoprotein (MAG, Siglec-4), were screened for their binding affinity for CD22 by surface plasmon resonance. The best compound identified was further modified with various hydrophobic substituents at the 2-, 5-, and 9-positions of the sialic acid scaffold, leading to nanomolar derivatives. Furthermore, initial tests regarding drug-like properties of these antagonists demonstrate the required high plasma protein binding yet a lack of oral availability, although its distribution coefficient (log D) is in the required range. Finally, we investigated a library of sialic acid mimetics with respect to binding towards another member of the Siglec family, namely Sialadhesin and discuss the influence of various structural moieties with regard to the arising selectivity towards these three proteins

From the ganglioside GQ1ba to glycomimetic antagonists of the myelin-associated glycoprotein (MAG)

The tetrasaccharide 4, a substructure of ganglioside GQ1bα, shows a remarkable affinity for the myelinassociated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Galβ(1-3)GalNAc, as well as the terminal α(2-3)- and the internal α(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17

Amino Acid-Based reoxidants for aminohydroxylation: Application to the Construction of Amino Acid–Amino Alcohol Conjugates

A viable nitrogen source for the aminohydroxylation reaction of terminal alkenes: By adding a N-O based reoxidant onto an amino acid acyl carbon atom, compounds were obtained that facilitated catalytic turnover and also promoted the conjugation of an amino acid with an alkene. High levels of regioselectivity were observed, as well as good stereoselectivity induced by catalytic amounts of a chiral ligand.Depto. de Química en Ciencias FarmacéuticasTRUEpu