Towards the synthesis of a CNS-active galectin-3 inhibitor in the form of a galactopyranose-depleted variant of a macrocyclic drug lead.

Abstract

The design and development of drugs which can permeate the blood brain barrier (BBB) for the treatment of hard-to-treat central nervous system (CNS) diseases is a critical and prevalent challenge in medicinal chemistry. Such diseases include Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) - both chronic and progressive neurodegenerative disorders affecting the brain. Galectin-3 (gal-3) is a carbohydrate binding protein which has been shown to be associated with some of the major hallmark pathologies of both of these diseases.

This project focuses on the synthesis towards a target compound, a sugar-depleted non-carbohydrate mimic of a previously synthesised carbohydrate macrocycle, aimed at targeting and inhibiting gal-3 for the treatment of CNS diseases.

Key steps in the synthesis were established, and a viable synthetic route was elucidated towards the synthesis of the target compound, starting from commercially available D-galactose. Work carried out previously in the group was successfully reproduced to prepare four intermediate compounds - highlighting the reliability of these procedures. Intermediates were purified where appropriate and analysed by nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography mass spectrometry (LC-MS). Two novel compounds were synthesised and characterised.

Further work is required to complete the synthesis of the target macrocycle and conduct biophysical studies to ascertain its binding thermodynamics and BBB permeability. These results can then be compared with those of the reference macrocycle, of which the target compound was designed to be a non-carbohydrate mimic.

This work demonstrates steps in a feasible synthetic route to a novel gal-3 inhibitor.

Popular Abstract

CNS diseases affect the brain and spinal cord, and it was estimated that in 2021, 3.4 billion people worldwide were affected by a nervous system condition – this was 43 % of the population. There are different types of CNS diseases which can be generalised into broad classes including autoimmune diseases and vascular diseases. This work focuses on neurodegenerative CNS diseases. Characterised by the progressive loss of nerve cells or neurons in the brain/spinal cord, neurodegenerative disorders lead to a functional decline of the affected area and a gradual worsening of quality of life. Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two examples of neurodegenerative disorders. AD affects cognitive function and memory whilst PD affects movement and motor skills. Both diseases are associated with neuroinflammation and microglial dysregulation, as well as other individual hallmark pathologies.

They are considered to be hard-to-treat diseases, as their location in the brain means that drug compounds must access the brain to exercise their effect. This involves the crossing of the BBB, which is a highly selective defence system that the body has in place to protect the brain and prevent potentially harmful compounds gaining access to it. Compounds must pass through the cells in this lipophilic membrane, meaning that permeability is favoured by increased lipophilicity and decreased polarity.

Galectins are a family of 15 different types of carbohydrate binding protein. Gal-3 is a unique member of the family as it is the only galectin which is a “chimera” type galectin. This means that is possesses two types of domains instead of just one - this makes it an attractive drug target. Different studies have shown that gal-3 has been associated with some of the major features of AD and PD. For example, one study has shown that gal-3 expression was ten times higher in the brains of patients with AD than in those of healthy patients. As such, it is proposed that the targeting and blocking of this protein could hold therapeutic potential for treatment of these diseases.

The aim of this project was to develop a synthetic route towards the synthesis of a gal-3 inhibiting target macrocycle. This target compound is a non-sugar mimic based on a previously synthesised sugar containing macrocycle. The reasoning for creating a sugar-depleted variant of the reference macrocycle is that it is hypothesised that the removal of a portion of the sugar that is not involved in binding to the protein will decrease the polarity of the compound. This means that it might show improved tendencies for crossing the BBB.
The synthesis of the final compound was not achieved but key steps in the synthetic route towards the target compound were elucidated and two novel compounds were synthesised. Information on the viability of certain aspects of the synthetic scheme was gained and a clear plan for the continuation of the synthesis has been established.

• author: Hiney, Róisín Muireann
• supervisor: Ulf Nilsson
• organization: Centre for Analysis and Synthesis
• course: KASM20 20251
• year: 2025
• type: H2 - Master's Degree (Two Years)
• subject: Chemistry
• keywords: medicinal chemistry, galectins, galectin-3, galectin-3 inhibition, macrocycle, organic chemistry
• language: English
• id: 9201518
• date added to LUP: 2025-06-18 14:40:22
• date last changed: 2025-06-18 14:40:22