Oxidative activation of leinamycin E1 triggers alkylation of guanine residues in double-stranded DNA

Abstract

It may be useful to develop prodrugs that are selectively activated by oxidative stress in cancer cells to release cell-killing reactive intermediates. However, relatively few chemical strategies exist for the activation of prodrugs under conditions of oxidative stress. Here we provide evidence for a novel process in which oxidation of a thiol residue in the natural product leinamycin E1 by HO and other byproducts of cellular oxidative stress initiates generation of an episulfonium ion that selectively alkylates guanine residues in duplex DNA.

Transcriptional Profiling of Porcine Blastocysts Produced In Vitro in a Chemically Defined Culture Medium

“…Of this group of genes, the one that showed the greatest differences with respect to the IVV was MGMT , depicting fold change values above 8 in both the BSA and PF4 groups. This gene encodes for a protein responsible for accepting alkyl groups from damaged nucleotides and reestablishing their functionality [ 76 ], which has been demonstrated as a typical injury triggered by oxidative damage [ 77 ]. Other interesting genes involved in DNA repair were GADD45B [ 78 ], DDB1 [ 79 ] and POLB , which repair short patch base excisions [ 80 ].…”

Polyene Macrolactams from Marine and Terrestrial Sources: Structure, Production Strategies, Biosynthesis and Bioactivities

“…LNM, in particular, was demonstrated to have a distinct DNA-damaging mechanism of action involving activation by cellular thiols [132]. In the presence of sulfhydryl, a reductive cofactor, LNM, caused DNA alkylation, resulting in single-stranded DNA breaks [133]. Individual disulfide alkyl groups had different DNA shearing mechanisms in vitro compared with intact LNM [45].…”