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 ZnII into 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.