Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability

Title:Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability

Volume: 13 Issue: 1

Author(s): Patrick-Denis St-Coeur, Marc Cormier, Veronique C. LeBlanc, Pier Jr. Morin and Mohamed Touaibia

Affiliation:

Keywords: Glioblastoma multiforme, guanine analogs, temozolomide, lomeguatrib, MGMT.

Abstract: 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 TMZ.

Methods: Twenty-five O⁶-alkyl, 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-methylguanine DNAmethyltransferase 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 tumors.

Cite this article as:

St-Coeur Patrick-Denis, Cormier Marc, LeBlanc C. Veronique, Morin Jr. Pier and Touaibia Mohamed, Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability, Medicinal Chemistry 2017; 13 (1) . https://dx.doi.org/10.2174/1573406412666160710210907

DOI https://dx.doi.org/10.2174/1573406412666160710210907	Print ISSN 1573-4064
Publisher Name Bentham Science Publisher	Online ISSN 1875-6638