Patrick-Denis St-Coeur, Marc Cormier, Veronique C LeBlanc, Pier Jr Morin, Mohamed Touaibia1.
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 cells proliferation 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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
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 cells proliferation 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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.
Entities:
Keywords:
Glioblastoma multiforme; MGMT.; guanine analogs; lomeguatrib; temozolomide
Mesh：
Substances：
Year: 2016
PMID： 27396904 DOI： 10.2174/1573406412666160710210907
Source DB: PubMed Journal: Med Chem ISSN： 1573-4064 Impact factor: 2.745