We describe sequence-specific alkylation in the minor groove of double-stranded DNA by a hybridization-triggered reactive group conjugated to a triplex forming oligodeoxyribonucleotide (TFO) that binds in the major groove. The 24 nt TFOs (G/A motif) were designed to form triplexes with a homopurine tract within a 65 bp target duplex. They were conjugated to an N 5-methyl-cyclopropapyrroloindole...

Both chlorozotocin and 1-(2-chloroethyl)-3-cyclohexyl-1nitrosourea (CCNU) bind specifically to the extended euchromatin fraction of the HeLa cell genome. After a 2-hr incubation of log-phase cells with each radiolabeled drug at 30 /(M, both alkylation (chlorozotocin and CCNU) and carbamoylation (CCNU) of nuclear chromatin were shown to be confined to late-eluting fractions from an ECTHAMcellulo...

The alkylating agent 2-bromo-4'-nitroacetophenone (BrNAP) binds covalently to each of 10 isozymes of purified rat liver microsomal cytochrome P-450 (P-450a-P-450j) but substantially inhibits the catalytic activity of only cytochrome P-450c. Regardless of pH, incubation time, presence of detergents, or concentration of BrNAP, treatment of cytochrome P-450c with BrNAP resulted in no more than 90%...

The mutant mouse lymphoma cell line (L5178YAII), resistant to X-rays, ultraviolet light and alkylating agents, was reinvestigated in an attempt to establish the nature of the mutation. These cells were compared with P388 mouse lymphoma cells, which exhibit normal sensitivity to these mutagens. A series of studies was conducted to compare DNA alkylation and strand breakage with cell survival aft...

Molecular recognition and chemical modification of DNA are important in medicinal chemistry, toxicology, and biotechnology. Historically, natural products have revealed many interesting and unexpected mechanisms for noncovalent DNA binding and covalent DNA modification. The studies reported here characterize the molecular mechanisms underlying the efficient alkylation of duplex DNA by the Strep...

Protein alkylation by 4-hydroxy-2-nonenal (HNE), an endogenous lipid derived electrophile, contributes to stress signaling and cellular toxicity. Although previous work has identified protein targets for HNE alkylation, the sequence specificity of alkylation and dynamics in a cellular context remain largely unexplored. We developed a new quantitative chemoproteomic platform, which uses isotopic...

Hydroxyhalofuranones form a group of genotoxic disinfection byproduct (DBP) of increasing interest. Among them, mucohalic acids (3,4-dihalo-5-hydroxyfuran-2(5H)-one, MXA) are known mutagens that react with nucleotides, affording etheno, oxaloetheno, and halopropenal derivatives. Mucohalic acids have also found use in organic synthesis due to their high functionalization. In this work, the alkyl...