The synthesis of multivalent glycomimetics for the improved treatment of glioblastoma multiforme

Glioblastoma Multiforme (GBM) is a fatal form of malignant brain tumour that is complicated to treat due to its heterogeneity and therapy resistance.1 The standard treatment is to surgically remove as much of the tumour as safely possible and place a chemotherapy directly into the resection site; undoubtedly an invasive and potentially damaging procedure. Activation of complement system (CS) following brain injury is a major contributor to secondary brain damage.2 Studies have shown that inhibition of Mannose Binding Lectin (MBL), an activator of the CS, can reduce the loss of sensorimotor capabilities after traumatic brain injury or stroke.3 This project seeks to improve treatment outcomes by taking advantage of this cerebral protective effect, via the formulation of biodegradable chemotherapeutic hydrogels with MBL inhibitors. To prepare the hydrogels, the multivalent pseudo-dimannoside MBL inhibitor (Fig. 1-A) was synthesised at half gram scale, alongside a new generation of potentially more stable glycomimetic inhibitors (Fig.1-B).4 Their tetravalent scaffold linked to a pseudodisaccharide is believed to be a key factor in affinity for the MBL’s oligomeric binding site (Fig 1-C). The goal of this work is to reduce treatment-related complications of GBM tumour removal and establish MBL’s potential as a therapeutic target to minimize surgical brain damage.