Figure 2. Plot of the SNAr reaction profiles
for compounds 2 , 4 and
18 .
It should be acknowledged that such analyzes are further complication by
the fact that the LLNA response is not always a result of direct
sensitization the molecule itself, rather an effect of reactive
metabolites. This issue further complicates the construction and
validation of computational methodologies such as these reported
here.[21,
64] In particular, it is known that 1,2
diones such as compound 16 , glyoxal are not commonly
encountered because it can form a hydrate, which can then undergo
oligomerization.
3.2 Reaction Barriers vs LLNA
pEC3
The goal of the present work is to determine whether it is possible to
attribute the skin sensitization to the predicted chemical reactivity of
the functional groups present the molecules1-22 . We first assessed whether a relationship
existed between the predicted barriers to reaction and the skin
sensitivity. The expectation was that TS2 should show the most
significant correlation with the LLNA pEC3 given that this was almost
exclusively the rate determining barrier for the molecules studied here.
Indeed we did see the strongest correlation between the TS2 (lowest
value of the reported positions if more than one) and the pEC3. However,
when all 22 compounds were included, the observed correlation
coefficient squared (r2) was just 0.16. This prompted
us to re-evaluate the data by excluding compound 18 ,
which is a predicted to be a strong sensitizer via the
SNAr domain, and the 1,2 dione compound
(5, 9, 16, 17, 20 ),
which potentially exist in their hydrated form. This is similar to the
approach of Roberts et al. who focused on compounds with a single
reactive group consisting primarily of aldehydes and ketones and may
point to a need for a more restricted domain of
applicability.[32]
Re-analysis of the correlation between the 16 remaining compounds and
the pEC3 reveals an improved, albeit weak correlation, with an
r2 of 0.36. It is found as the predicted barrier to
reaction decreases, the experimental sensitization is found to increase
in line with expectation (Figure 2). It can also be seen from Figure 3
there is a lipophilicity effect operating within the dataset. Compounds,
which have been colored by logP, show a noticeable trend in that, those
with a higher logP generally have lower pEC3 for a given barrier. For
example, the 1,3 dione 8 has a predicted barrier of
approximately 22 kcal/mol compared to 19 which has a
barrier of ~25 kcal/mol (19 a). This
would suggest that 8 should be a stronger sensitizer
than 19 , whereas in fact the opposite is observed (pEC3
of 0.84 vs 1.97, respectively). The predicted logP of 8
is 3.93 while that of 19 is 1.28 suggesting that a lower
barrier combined with a low logP leads to increased sensitization for
this set of diverse compounds.
This observation apparently contradicts the findings of the earlier QSAR
study of Roberts et al. on Schiff
bases.[32] However, since this
publication, the authors have reported an extensive analysis of 525
substances and note that logP is not simply a surrogate for permeability
and that higher logP values do not result in higher sensitization on a
diverse set of compounds.[65] The
result is also consistent with observations that the Schiff base,
formaldehyde (logP=-0.51), which is known to be highly sensitizing in
sensitization based-assays. [66] It
should be noted that we are using a somewhat larger (22
vs 16 compounds), and more diverse set of chemicals
(70% were aldehydes in the latter study). Indeed evidence for similar
series specific-logP behavior can be seen from the non-linear
relationship between logP and pEC3 for azlactones of the acyl
domain.[5]