The Potential of Memantine Sulfonamides in Glioblastoma Treatment

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults. Treatment for GBM often involves a combination of surgery, radiation therapy, and chemotherapy. Surgery aims to remove as much of the tumor as possible, while radiation and chemotherapy are used to kill remaining cancer cells and slow the tumor’s growth. However, complete removal of the tumor is often not possible due to its location and invasive nature. The prognosis for GBM is generally poor, with a median survival of about 15 months after diagnosis, though this can vary based on several factors including age, overall health, and the success of treatment. There is an urgent medical need for better treatments for GBM.  To address this challenge, a new study published in the journal ChemMedChem by John Philo, Jenna Caudle, Reema Moussa, Patrick Kampmeyer, Tasfia Hasin, David Seo, and led by Professors Robert Sheaff and Angus Lamar from the Department of Chemistry and Biochemistry at the University of Tulsa, the researchers designed novel compounds capable of targeting GBM effectively. They recognized two major hurdles in developing such drugs: the heterogeneity of GBM and the need for compounds to cross the blood-brain barrier (BBB). To tackle these challenges, the team turned to memantine, a drug known for its ability to cross the BBB and its potential as a scaffold for designing novel GBM-targeting compounds.

The researchers initiated their investigation by synthesizing a library of 34 memantine sulfonamides using two distinct methods. These methods allowed for the introduction of various aromatic substituents on the sulfonamide unit. The choice of these substituents was crucial, as it enabled the researchers to explore the electronic variations and potential binding interactions that could impact the compounds’ activity against GBM cells. The synthesized library of memantine sulfonamides was then subjected to rigorous in vitro biological evaluation to determine their cytotoxicity and selectivity. The authors selected four different mammalian cell lines were used in this evaluation, U-87 (glioblastoma): this cell line represented the primary target for the study, as the researchers aimed to develop compounds specifically effective against GBM. A549 (lung cancer): An additional cancerous cell line was included to assess the compounds’ broader cytotoxicity. MCF10A (non-cancerous breast epithelial cells): This non-cancerous cell line served as a control to evaluate the compounds’ selectivity for cancer cells. HDF (human diploid fibroblast): Another non-cancerous, immortalized cell line was used to further assess selectivity.

Additionally, the researchers predicted the BBB permeation of the compounds by plotting experimentally obtained lipophilicity values (LogP) against the topological polar surface area (TPSA). A BBB permeation model, known as the BOILED-Egg model, was employed to predict the compounds’ ability to cross the BBB. Among the 34 memantine sulfonamides tested, 11 compounds demonstrated cytotoxic activity against U-87 cells, meeting the criteria of being considered “hits.” These hits included compounds 1, 2, 5, 8, 9, 11, 12, 18, 24, 28, and 29. Importantly, all 11 identified hits were predicted to be BBB-permeable based on their experimentally obtained LogP values and calculated TPSA values. This suggests that these compounds have the potential to effectively reach brain cancer cells, a crucial attribute for GBM treatment.The authors found compounds 5 and 28 to exhibit notable selectivity for GBM cells (U-87) over non-cancerous HDF cells, making them particularly promising candidates for further investigation and potential optimization. The study uncovered intriguing structure-activity relationships, revealing the critical importance of the sulfonamide functionality and the memantine core in determining the compounds’ activity against GBM cells. In silico molecular docking studies were conducted to explore the potential binding interactions of the compounds with kinase proteins associated with glioblastoma. While no direct correlation between binding affinity and biological activity was observed, compounds targeting DDR1 and RET showed promising binding interactions, suggesting potential modes of action for these compounds.

In summary, the findings of Professors Robert Sheaff and Angus Lamar and their teams highlight the importance of the sulfonamide functionality and the memantine core in the design of these compounds. By comparing sulfonamide analogs with amide counterparts and exploring variations in the adamantane core, the researchers have identified critical structural features that contribute to the compounds’ activity against GBM cells. Moreover, the library of memantine sulfonamides displayed significant selectivity toward GBM cells while sparing non-cancerous cells, a crucial aspect of developing effective cancer treatments with minimal side effects. Compounds 5 and 28, in particular, exhibited promising selectivity for GBM over non-cancerous cells, making them potential candidates for further optimization.