Reactivity of p-nitrostyrene oxide as an alkylating agent. A kinetic approach to biomimetic conditions

Abstract

The alkylating potential of p-nitrostyrene oxide (pNSO)--a compound used as a substrate to study the activity of epoxide hydrolases as well as in polymer production and in the pharmaceutical industry--was investigated kinetically. The molecule 4-(p-nitrobenzyl)pyridine (NBP), as a model nucleophile for DNA bases, was used as an alkylation substrate. In order to gain insight into the effect of the hydrolysis of pNSO, as well as the hydrolysis of the NBP-pNSO adduct on the pNSO alkylating efficiency, these two competing reactions were studied in parallel with the main NBP-alkylation reaction. The following conclusions were drawn: (i) pNSO reacts through an S(N)2 mechanism, with NBP to form an adduct, pNSO-NBP (AD). The rate equation for the adduct formation is: r = d[AD]/dt = k(alk)[NBP][pNSO]-k(hyd)(AD) [AD] (k(alk), and k(hyd)(AD) being the alkylation rate constant and the NBP-pNSO adduct hydrolysis rate constant, respectively); (ii) the alkylating capacity of pNSO, defined as the fraction of initial alkylating agent that forms the adduct, is similar to that of mutagenic agents as effective as β-propiolactone. The instability of the pNSO-NBP adduct formed could be invoked to explain the lower mutagenicity shown by pNSO; (iii) the different stabilities of the α and β-adducts formed between NBP and styrene oxides show that the alkylating capacity f = k(alk)[NBP]/(k(alk)[NBP] + k(hyd)) (k(hyd) being the pNSO hydrolysis rate constant) as well as the alkylating effectiveness, AL = f/k(hyd)(AD), are useful tools for correlating the chemical reactivity and mutagenicity of styrene oxides; (iv) a pNSO-guanosine adduct was detected.

The reactivity of vinyl compounds as alkylating agents

“…In previous work we studied the in vitro reactivity of several alkylating compounds capable of forming DNA adducts: sorbic acid [4] and sorbates [5], nitrosoureas [6,7], p-nitrostyrene oxide [8], and lactones [9][10][11][12]. The results revealed a correlation between the carcinogenicity of the substances and their reactivity with 4-(p-nitrobenzyl)pyridine (NBP), a trap for alkylating agents with nucleophilicity similar to that of DNA [13,14].…”

Alkylating Potential of Styrene Oxide: Reactions and Factors Involved in the Alkylation Process

“…Assignment of the UFLC-DAD peaks was performed by comparison of their retention times, UV–vis spectra, and kinetic profiles with those of the β-adduct formed between NBP and p -nitrostyrene oxide, a substituted styrene oxide whose alkylating potential has been studied by us previously . The adducts identified were α-NBP–SO (AD unα ), t R = 11.0 min, and β-NBP–SO (AD unβ ), t R = 8.5 min (see Scheme ).…”

“…6,13,19,20,25 Assignment of the UFLC-DAD peaks was performed by comparison of their retention times, UV−vis spectra, and kinetic profiles with those of the β-adduct formed between NBP and p-nitrostyrene oxide, a substituted styrene oxide whose alkylating potential has been studied by us previously. 26 The adducts identified were α-NBP−SO (AD unα ), t R = 11.0 min, and β-NBP−SO (AD unβ ), t R = 8.5 min (see Scheme 1). These two types of adduct also result in alkylation at the N-7 position in the reaction between SO and guanosine, deoxyguanosine, and the single-or double-stranded DNA in vitro under physiological conditions.…”

Nucleophilic Aliphatic Substitution

“…46 Energy barriers, calculated from experimental data and theoretically at the B3LYP/6-31++G(d,p) level in the gas phase and using the IEFPCM (integral equation formalism -polarisable continuum model) self-consistent reaction field method in solution, indicate that the attack by nitrogen which accounts for 80-90% of the product in the pH range 4.5-7, occurs at the least-substituted carbon. Activation parameters are given for the alkylation reaction.…”

“…These include using B3LYP/6-31+G** calculations in the gas phase and the PCM model in solution to predict how lactone enolates react with allyl carbonates in the presence of [Pd 2 (dba) 3 ]-CHCl 3 , BINAP, and LiCl in THF; 12 employing DFT/MO6 de calculations with a polarized Boltzmann SCRF model in solution to model the Pdcatalysed intramolecular asymmetric allylic alkylation of unsaturated amides giving trans-γ -and δ-lactams; 13 using MP2/6-31G(d)//HF/3-21G* calculations to model ee the tandem S N 2 /S N 2 reaction converting Morita-Baylis-Hillman acetates into γbutenolides with 2-trimethylsilyloxyfuran in the presence of a chiral amide-phosphane organocatalyst; 28 determining the rates and energy barriers for the S N 2 hydrolysis ee and alkylation reaction between para-nitrostyrene and 4-(para-nitrobenzyl)pyridine at the B3LYP/6-31++G(d,p) level of theory in the gas phase and by applying the IEFPCM self-consistent reaction field method in solution; 46 examining the hydrolysis of epichlorohydrin in neutral and acidic conditions at the UB3LYP/6-311++G(d,p) level of theory; 47 calculations at the B3LYP/6-31+G(d) level to show that the S N 2 ring-opening reaction of ethylene oxide by ammonia is catalysed by BF 3 but not by BH 3 ; 50 and to show how substituents conjugated with the epoxide ring affect the bonding, electron density at the reacting atoms, atomic charges on the atoms, the source function, and the intermolecular interactions in the ring-opening reaction; 51 using calculations at the B3LYP/6-311+G(d,p) level in the gas phase and the IEFPCM model to account for the solvent in the regiospecific S N 2 ring opening of ortho-and para-nitroor 2,4-dinitrophenylglycidyl ethers when treated with bicyclo[2.2.1]hept-5-ene-endo-2ylmethylamine in 2-propanol; 53 MPWB1K/6-311++G(3df,2p) calculations indicating that the conversion of CO 2 to cyclic carbonate occurs by the termolecular, regioselective, S N 2 reaction between an N-heterocyclic carbene, 2-methylethylene oxide, and CO 2 ; 58 using MPW1K/6-31++G(d,p)//B3LYP/6-31++G(d,p) calculations to study the S N 2 reactions of N-benzyl-2-bromomethylaziridine, N-tosyl-2-bromomethylaziridine, and 2-bromomethyloxirane with methoxide ion in the gas phase and in methanol using the supermolecule approach; 65 employing M06-2X/6-311+g(2df,2p)//B3LYP/6-31G(d,p) calculations to determine the mechanism of the thiol or carbamodithiolic acid -amino-indoanol-derived guanidine catalyst ring opening of meso-aziridines; 71 ee de studying the reaction between N-methyl, N-2-chloroethyl aziridinium ion and quanine at the ring carbon using B3LYP/ 6-311++G(d,p) calculations in the gas phase and the PCM model in water; 73 and investigating the effect of substituents, nucleophiles, Lewis acids, and solvents on the regioselectivity of the silver ion-catalysed S N 2 ring opening of thiiranes with ammonia or primary amines at the B3LYP/IEFPCM/6-311++G(d,p)&LAN2DZ//B3LYP/6-31+G(d,p)&LAN2DZ level of theory. 74 The IEF-PCM/B3LYP/BS method was used to calculate the rate of reaction in methanol.…”