), on the other hand, were recently shown to be compounds capable of inducing cellular-protecting enzymes such as the phase II enzymes when provided in moderate concentrations.
The region-selectivity of nucleophilic center is governed by the nature of the electrophiles
and the pH of the reaction medium .
As indicated above, soft electrophiles
such as ACR preferentially react with soft nucleophiles.
Effects of selenium deficiency on the formation and detoxification of endogenous electrophiles
The compounds 1-3 containing [alpha],[beta] -unsaturated esters are electrophiles
. It was therefore thought that if the [alpha],[beta]-unsaturated ester moiety is incorporated into the basic structural frame of a simple substrate in such a way that it would bind the enzyme with its carbonyl group being coordinated to the zinc ion, then a Michael type addition reaction may occur on the [alpha],[beta]-unsaturated acid or ester by the catalysed carboxylate in ACE, leading to irreversible inhibition of the enzyme.
In other words, reaction 15 occurs because CpCr[(NO).sub.2] Me is relatively difficult to oxidize and its Cr-[CH.sub.3] bond is prone to nonoxidative attack by electrophiles
. Indeed, we have shown subsequently that insertions analogous to that depicted in eq 15 can be effected for a variety of CpCr[(NO).sub.2 R] complexes (R = Me, CH.sub.2 SiMe.sub.3], Or Ph) and several electrophiles
NE+ (E = [O, p-O.sub.2 NC.sub.6 H.sub.4 N,] or S).
This results in stabilization and increased levels of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) by means of Kelch-like ECH-associated protein 1 (KEAP1) which normally targets Nrf2 for ubiquitination and degradation but loses this ability in response to electrophiles
and oxidants [16, 17].
The obtained solid precipitates were collected through filtration followed by washing with cold distilled water and drying at RT to yield corresponding electrophiles
, N-substituted-2- bromoacetamides, 6a-f.
The synthesis of imidazo[1,2-b]pyrazoles was reported; thus the condensation of the hydrazinoacetaldehyde synthon with electrophiles
such as ethyl (ethoxymethylene)cyanoacetate 2 and 3-oxo-2-phenylpropanenitrile 9 gave ethyl 5-amino-1-(2,2-diethoxyethyl)-1H-pyrazole-4-carboxylate 10 and 1-(2,2-diethoxyethyl)-4-phenyl-1Hpyrazol-5-amine 12, respectively.
When cells are exposed to electrophiles
or oxidants, modification of the sulthydryl groups in KEAP1 occurs, liberating NRF2 from KEAP1-mediated degradation, and NRF2 accumulates in the nucleus (Dinkova-Kostova et at 2002; Motohashi and Yamamoto 2004).
An unexpected new property of tetrapyrroles, including tetramethyl coproporphyrin III, tetrabenzoporphine, copper chlorin e4 ethyl ester, and of carotenoids including zeaxanthin and alpha-cryptoxanthin is their ability to induce mammalian phase 2 proteins that protect cells against oxidants and electrophiles
. The capacity of these compounds to induce the phase 2 response depends upon their ability or that of their metabolites to react with thiol groups, a property shared with all other classes of phase 2 inducers, which show few other structural similarities.
It functions by detoxifying electrophiles
and scavenging free radicals, consequently producing GSSG.