PMID- 24397518
OWN - NLM
STAT- MEDLINE
DCOM- 20141113
LR  - 20140217
IS  - 1520-5010 (Electronic)
IS  - 0893-228X (Linking)
VI  - 27
IP  - 2
DP  - 2014 Feb 17
TI  - Electrophilic reactivity and skin sensitization potency of SNAr electrophiles.
PG  - 240-6
LID - 10.1021/tx400355n [doi]
AB  - We published in 2011 a quantitative mechanistic model (QMM) for skin 
      sensitization potency of SNAr electrophiles in the mouse local lymph node assay 
      (LLNA). In this model, potency was correlated with a combination of sigma* for the 
      leaving group and the total sigma(-) values of the other substituents in the aromatic 
      ring. Shortly afterward Natsch et al. published a kinetic study in which rate 
      constants were determined for reactions of SNAr electrophiles with the 
      cysteine-based peptide Ac-RFAACAA (Cys-peptide) that is used in the direct 
      peptide reactivity assay (DPRA), and correlations were sought between these rate 
      constants and sensitization potency in the LLNA. These two publications together 
      have enabled the present study, aiming to develop a linear free energy 
      relationship (LFER) correlating Cys-peptide reactivity with a reactivity 
      parameter (RP) based on a combination of sigma* and sigma(-) substituent constants and, 
      by analyzing differences between the QMM based on RP and the QMM based on 
      Cys-peptide rate constants, to gain further insights into the underlying 
      chemistry of skin sensitization. For the 2,4-dinitro-X-subsituted benzenes 
      (DNXB), the rate constants of Natsch et al. are well correlated with the 
      reactivity parameter used in our earlier work, with two outliers. These are the 
      compounds with X = F and X = SCN, which are both substantially more reactive 
      toward Cys-peptide than predicted from comparison of their RP values with those 
      of the other DNXB compounds. These two compounds are both negative outliers from 
      a correlation of sensitization potency with experimental rate constants, but fit 
      well to the correlation of sensitization potency with RP values. With these two 
      compounds excluded, sensitization potency is well correlated with the 
      experimental rate constants for the DNXB compounds (X = SO3(-), I, Br, Cl) 
      together with 2,4-dichloro-1-nitrobenzene and 
      1,3,4,5-tetrachloro-2,6-dicyanobenzene. The regression equation is pEC3 = 0.88 
      log k + 4.03, R(2) = 0.966. The implication of DNFB being an outlier is that the 
      model Cys-peptide nucleophile is substantially more sterically hindered than the 
      cutaneous nucleophile(s) involved in the sensitization process. The pattern seen 
      with 2,4-dinitrothiocyanatobenzene suggests that this compound reacts as an SNAr 
      electrophile in the sensitization process, but by a different pathway, acting as 
      a CN transfer agent, with the model Cys-peptide. For two further compounds, 
      2,4,6-trinitrochlorobenzene and 2,4,6-trinitrobenzenesulfonate, the Cys-peptide 
      rate constants are well predicted by the reactivity parameter based on 
      displacement of the Cl or SO3(-) substituent, but their sensitization potency is 
      underestimated by both the Cys-peptide rate constant and this reactivity 
      parameter. However, potency of these two compounds is well predicted by a 
      reactivity parameter calculated on the basis of displacement of the 2-nitro 
      group. This is interpreted as a case of sensitization being driven by the 
      thermodynamically favored rather than the kinetically favored reaction product.
FAU - Roberts, D W
AU  - Roberts DW
AD  - School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University , 
      Byrom Street, Liverpool L3 3AF, England.
FAU - Aptula, A O
AU  - Aptula AO
LA  - eng
PT  - Journal Article
DEP - 20140121
PL  - United States
TA  - Chem Res Toxicol
JT  - Chemical research in toxicology
JID - 8807448
RN  - 0 (Allergens)
RN  - 0 (Nitrobenzenes)
RN  - 0 (Peptides)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Allergens/*chemistry/toxicity
MH  - Cysteine/*chemistry
MH  - Dermatitis, Allergic Contact/etiology
MH  - *Models, Biological
MH  - Nitrobenzenes/*chemistry/toxicity
MH  - Peptides/*chemistry
EDAT- 2014/01/09 06:00
MHDA- 2014/11/14 06:00
CRDT- 2014/01/09 06:00
PHST- 2014/01/09 06:00 [entrez]
PHST- 2014/01/09 06:00 [pubmed]
PHST- 2014/11/14 06:00 [medline]
AID - 10.1021/tx400355n [doi]
PST - ppublish
SO  - Chem Res Toxicol. 2014 Feb 17;27(2):240-6. doi: 10.1021/tx400355n. Epub 2014 Jan 
      21.