title: Effect of O6-Substituted Guanine Analogs on O6-methylguanine DNA-methyltransferase Expression and Glioblastoma Cells Viability.
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).
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Patrick-Denis
authors.initials: PD
authors.lastname: St-Coeur
authors.forename: Marc
authors.initials: M
authors.lastname: Cormier
authors.forename: Veronique C
authors.initials: VC
authors.lastname: LeBlanc
authors.forename: Pier Jr
authors.initials: PJ
authors.lastname: Morin
authors.affiliation: Department of Chemistry and Biochemistry, Universite de Moncton, Moncton, New Brunswick, Canada E1A 3E9.. Canada.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Touaibia
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015254:DNA Modification Methylases; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006147:Guanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006147:Guanine; C008449:O-(6)-methylguanine; D015254:DNA Modification Methylases
keywords: Glioblastoma multiforme; MGMT.; guanine analogs; lomeguatrib; temozolomide