Background: Glioblastoma multiforme (GBM) is often associated with a poor survival
prognostic for patients. The main reason seems to be the acquired or inherent resistance to the chemotherapeutic
agent used to treat the tumor, temozolomide (TMZ). To this day, the most recognized
pathway of resistance is the DNA Direct Repair pathway by the means of the protein O6-
methylguanine DNA-methyltransferase (MGMT).
Objectives: To design and synthesize a series of MGMT inhibitors that can sensitize GBM cells to
Methods: Twenty-five O6
-aryl and O6
-substituted-aryl guanine analogs including nine
novel compounds were synthesized, characterized, analyzed by molecular docking and tested on the
T98G GBM cells viability.
Results: Following molecular modeling with MGMT, the newly designed compounds 19, 22, and 24
emerged as the most promising MGMT ligands and displayed modest cytotoxicity. Guanine analog
(19), bearing a p-nitrobenzyl moiety, reduced considerably the O6
expression level. When combined with TMZ (1), which is used as first line treatment
for brain tumors, compounds 19, 22, and 24 decreased T98G cellsproliferation by 32%, 68%
and 50%, respectively. TMZ (1) displayed negligible effect on the proliferation of these cells further
supporting the notion that this cell model is resistant to this alkylating agent.
Conclusion: Overall, these results notably highlight a group of MGMT inhibitors that warrants further
exploration in the development of therapeutic options to circumvent TMZ resistance in brain