The synthesis of multivalent Mannose Binding Lectin Inhibitors for the treatment of Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) is the deadliest form of primary malignant brain tumour, with median survival rates post diagnosis being a meagre 14 months. Treatment of GBM remains complicated due to its heterogeneity and therapy resistance.[1] The conventional method of treatment is to surgically remove as much of the tumour as safely possible and place a chemotherapy directly into the resection cavity; undoubtedly an invasive and potentially damaging procedure. Activation of the complement system (CS) following brain injury is a major contributor to secondary brain damage.[2] Studies have shown that inhibition of the mannose binging lectin (MBL), an activator of the CS that is expressed following traumatic brain injury, can reduce the loss of sensorimotor capabilities after traumatic brain injury or stroke.[3] This project seeks to improve treatment outcomes by producing biodegradable chemotherapeutic hydrogels that can be moulded into the resection site and contain MBL inhibitors, to take advantage of their potentially cerebral protective effects. To evaluate this hypothesis, the multivalent pseudo-dimannoside MBL inhibitors (Fig. 1) were synthesised at half-gram scale.[4] Their tetravalent scaffold linked to a pseudo-disaccharide is believed to be a key factor in affinity for the MBL’s oligomeric binding site. 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.