Recognition and Cleavage of DNA

Functional Analogs of Bleomycin

Abstract

Bis-intercalators and hemin-intercalators (Hemin-Glu-P-1's) which recognize and/or cleave DNA were designed and synthesized. 2-Aminodipyrido [1, 2-a : 3', 2' -d] imidazoles (Glu-P's) which are potent muta-carcinogens isolated from a pyrolysate of L-glutamic acid were used as intercalator moieties. Bis-intercalators possess extremely high affinity toward double stranded DNA and stabilize the double helix structure of DNA from heat denaturation effectively. Hemin-Glu-P-1's cleaved DNA at G-C and G-T sequences preferentially. Glu-P-1 moiety which recognizes DNA by intercalation and a functional group which can be an intramolecular fifth ligand of the ferrous ion in the hemin moiety are required for strong DNA-cleaving ability. The mode of DNA-cleaving reaction of Hemin-Glu-P-1's is quite similar to that of bleomycin (BLM). In other words, Hemin-Glu-P-1's are functional analogs of BLM. The mechanism of DNA cleavage by Hemin-Glu-P-1's and by BLM is not single. One of the mechanisms involves two bases elimination from the DNA.