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Impact of the Acetyl Group on Cysteine: A Study of N‐Acetyl‐Cysteine through Rotational Spectroscopy

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Sergio Mato at Universidad de Valladolid| Uva
Sergio Mato
  • Universidad de Valladolid| Uva
S. Municio
S. Municio
S. Municio
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José L Alonso at Universidad de Valladolid
José L Alonso
E. R. Alonso
E. R. Alonso
E. R. Alonso
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Abstract and Figures

Herein, we report a spectroscopic study of N‐acetyl‐L‐cysteine, an important antioxidant drug, using Fourier‐transform microwave techniques and in isolated conditions. Two conformers are observed, where most stable structure adopts a cis disposition, and the second conformer has a lower abundance and adopts a trans disposition. The rotational constants and the barriers to methyl internal rotation are determined for each conformer, allowing a precise conformation identification. The results show that the cis form adopts an identical structure in the crystal, solution, and gas phases. Additionally, the structures are contrasted against those of cysteine.
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Impact of the Acetyl Group on Cysteine: A Study of
N-Acetyl-Cysteine through Rotational Spectroscopy
S. Mato,[a] S. Municio,[a] J. L. Alonso,[a] E. R. Alonso,[a] and I. León*[a]
Herein, we report a spectroscopic study of N-acetyl-L-cysteine,
an important antioxidant drug, using Fourier-transform micro-
wave techniques and in isolated conditions. Two conformers
are observed, where most stable structure adopts a cis
disposition, and the second conformer has a lower abundance
and adopts a trans disposition. The rotational constants and the
barriers to methyl internal rotation are determined for each
conformer, allowing a precise conformation identification. The
results show that the cis form adopts an identical structure in
the crystal, solution, and gas phases. Additionally, the structures
are contrasted against those of cysteine.
Introduction
Many health conditions, such as neurodegeneration, diabetes,
and cancer, originate from oxidative stress. Oxidative stress
arises from an imbalance between free radicals generated
during various cellular processes and the body‘s antioxidants.
This imbalance is particularly concerning as free radicals bind to
essential cellular components such as DNA, RNA, lipids, and
proteins, disrupting the antioxidant defense system, redox
homeostasis, interfering with cellular signaling, and altering the
functionality of these biomolecules.[1–3] Hence, antioxidant drug
development has been increasing over the years for addressing
these diseases and has been effectively employed for their
treatment.
N-acetyl-L-cysteine (NAC, see Figure 1) is an important
antioxidant drug included in the WHO Model List of Essential
Medicines.[4] NAC is a L-cysteine (Cys) derivative, as well as a
precursor of glutathione (GSH), an endogenous antioxidant (see
Figure 1). NAC follows different mechanisms within the organ-
ism to act as an antioxidant.[5] On the one hand, NAC can act as
a direct antioxidant where the free thiol group, in its active
thiolate form, reacts with oxygen and nitrogen species (RONS).
However, among all endogenous antioxidants, NAC is consid-
ered relatively weak. Conversely, NAC can also function as an
indirect antioxidant by replenishing GSH levels in the organism.
Moreover, the administration of NAC promotes the incorpo-
ration of GSH, thereby neutralizing toxic byproducts resulting
from paracetamol metabolism. This property makes NAC a
widely employed drug for paracetamol overdose treatment.[5–7]
Aside from its antioxidant properties, NAC is also a potent
reducing agent for protein disulfide cross-links, utilizing the
classic thiol-disulfide interchange mechanism. This attribute is
responsible for its mucolytic activity, as it disrupts disulfide links
present in mucoproteins, reducing mucus viscosity. Conse-
quently, NAC has practical application in the treatment of
chronic bronchopulmonary disorders.[5–7] Additionally, NAC
demonstrates promising anti-inflammatory and metal-chelating
activities. Regarding anti-inflammatory properties, NAC func-
tions by inhibiting NF-kB, a key player in the inflammatory and
immune response triggered by oxidative stress. NAC effectively
mitigates inflammatory processes by preventing NF-kB trans-
location into the cell nucleus and activation genes associated
with inflammation. Furthermore, NAC reduces the release of
inflammatory cytokines in activated macrophages, including
TNFα, IL-1β, and IL-6. In metal chelation, NAC employs its thiol
group to bind to active redox metal ions, encompassing
transition and heavy metals such as mercury, cadmium,
chromium, arsenic, and gold. This results in the formation of
easily excretable complexes for the body.[7] Due to these
multifaceted properties, ongoing clinical studies are exploring
the potential of NAC in treating various psychiatry/neurology
disorders such as Alzheimer’s, anxiety, bipolar disorder, meta-
bolic syndrome (including diabetes), and other health
conditions.[7–10]
[a] S. Mato, S. Municio, J. L. Alonso, E. R. Alonso, I. León
Grupo de Espectroscopia Molecular (GEM), Edificio Quifima Laboratorios de
Espectroscopia y Bioespectroscopia, Parque Científico Universidad de
Valladolid, 47011, Valladolid, Spain
E-mail: iker.leon@uva.es
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/cphc.202400191
Figure 1. Chemical structure of N-acetyl-L-cysteine and its indirect antiox-
idant mechanism to convert it in GSH. GCS stands for the enzyme γ-
glutamylcysteine and GS stands for the enzyme Glutathione synthetase.
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