DNA-Targeted Inhibition of MGMT.
The cationic porphyrin 5,10,15,20-tetrakis (diisopropyl-guanidine)-21H,23H-porphine (DIGPor) selectively binds to DNA containing O6-methylguanine (O6-MeG) and inhibits the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). The O6-MeG selectivity and MGMT inhibitory activity of DIGPor were improved by incorporating ZnIIinto the porphyrin. The resulting metal complex (Zn-DIGPor) potentiated the activity of the DNA-alkylating drug temozolomide in an MGMT-expressing cell line. To the best of our knowledge, this is the first example of DNA-targeted MGMT inhibition.
Department of Chemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
Theodor
T
Marsoner
Department of Chemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
Olivia P
OP
Schmidt
Department of Chemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
Therese
T
Triemer
Department of Chemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
Nathan W
NW
Luedtke
D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D004247:DNA / Q000378:metabolism*; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D006147:Guanine; D003606:Dacarbazine; D004247:DNA; C008449:O-(6)-methylguanine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
MGMT; O6-methyl- guanine; drug discovery; inhibitors; porphyrin; temozolomide