Thiol-Activated DNA Damage by α-Bromo-2-cyclopentenone

Abstract

Some biologically active chemicals are relatively stable in the extracellular environment but, upon entering the cell, undergo biotransformation into reactive intermediates that covalently modify DNA. The diverse chemical reactions involved in the bioactivation of DNA-damaging agents are both fundamentally interesting and of practical importance in medicinal chemistry and toxicology. The work described here examines the bioactivation of α-haloacrolyl-containing molecules. The α-haloacrolyl moiety is found in a variety of cytotoxic natural products including clionastatin B, bromovulone III, discorahabdins A, B, and C, and trichodenone C, in mutagens such as 2-bromoacrolein and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and in the anticancer drug candidates brostallicin and PNU-151807. Using α-bromo-2-cyclopentenone (1) as a model compound, the activation of α-haloacrolyl-containing molecules by biological thiols was explored. The results indicate that both low molecular weight and peptide thiols readily undergo conjugate addition to 1. The resulting products are consistent with a mechanism in which initial addition of thiols to 1 is followed by intramolecular displacement of bromide ion to yield a DNA-alkylating episulfonium ion intermediate. The reaction of thiol-activated 1 with DNA produces labile lesions at deoxyguanosine residues. The sequence specificity and salt-dependence of this process is consistent with involvement of an episulfonium ion intermediate. The alkylated guanine residue resulting from the thiol-triggered reaction of 1 with duplex DNA was characterized using mass spectrometry. The results provide new insight regarding the mechanisms by which thiols can bioactivate small molecules and offer a more complete understanding of the molecular mechanisms underlying the biological activity of cytotoxic, mutagenic, and medicinal compounds containing the α-haloacrolyl group.

Analogues of the Epoxy Resin Monomer Diglycidyl Ether of Bisphenol F: Effects on Contact Allergenic Potency and Cytotoxicity

“…To confirm the latter result, a second experiment was performed in which both DGEBF and PGE were allowed to react simultaneously with the peptide. 51.5% of DGEBF-peptide adduct was formed compared to 48.5% of PGE-peptide adduct, confirming that DGEBF and PGE react with this peptide in essentially equimolar amounts.…”

“…23 The nature of the alkyl chain has a large impact on in vitro cytotoxicity when comparing monoaromatic compounds PGE and 4. PGE is known to cause cell death via reactive mechanisms, including DNA-damage, 48 activation of heat shock response and antioxidant response. 49 PGE forms DNA-adducts via its epoxide group, causing cytotoxicity and apoptosis.…”

Potential carcinogenic hazards of non-regulated disinfection by-products: Haloquinones, halo-cyclopentene and cyclohexene derivatives, N-halamines, halonitriles, and heterocyclic amines

“…These include halonitriles (Lin and Guion, 1989), halopropanoic acids (Tong et al, 1998a), chloropicrin , the halofuranones (Clark and Chipman, 1995;Febry et al, 2011), halopropanols (Hammond et al, 1999), halopropanones (Merrick et al, 1987) and as illustrated in this paper, the HQs. The isoforms of glutathione transferase involved in forming unstable or stable conjugates of some of these by-products have not been characterized.…”

Investigation of the electrophilic reactivity of the cytotoxic marine alkaloid discorhabdin B

“…discorhabdin C (3) 6 ). In the specific case of these analogues, natural products have been reported to contain Δ 16 unsaturation (e.g. discorhabdin Q (4) 7 ), or substitution at C-1 with further ring closure (e.g.…”