Autores
Zambrano, D. (UNIVERSIDAD EL BOSQUE) ; Guevara, J. (UNIVERSIDAD EL BOSQUE)
Resumo
Excessive UV exposure leads to skin pathologies such as sunburns, and carcinogenesis. Currently, sunscreen
use is the most important factor in protecting skin from photodamage. Octinoxate is a common UV filter, but
its use has recently been restricted in coastal areas around the world due to its detrimental effect on coral
reefs. Thus, this project sought to design an octinoxate analog that could be used as a less toxic, but equally
effective, photoprotective alternative through ligand based virtual screening. We designed 213 novel
molecules based on the (E)-cinnamoyl moiety of octinoxate. Then, an ANN-based model was built to predict
the molar absorptivity of those 213 molecules, and the molecule that presented a similar molar absorptivity to
that of octinoxate was chosen for synthesis.
Palavras chaves
ligand based virtual scre; molar absorptivity; artificial neural network
Introdução
Sunscreens are pharmaceutical products designed to help protect the skin against damage caused by UV
radiation, such as sunburns, skin cancer and photoaging (FLAVIA A. et al 204. 2022). These products are
made of UV filters that can
be classified into two main categories: inorganic filters (e.g zinc oxide, titanium dioxide) reflect the sun’s UV
radiation, while organic filters absorb it (e.g cinnamates, salicylates) (RUSZKIEWICZ JA, et al. 245. 2017.).
Octinoxate is a cinnamate derivative commonly used as a UVB filter in sunscreens and a variety of personal
care products. However, recent studies have shown that this compound is an endocrine disruptor in both
humans and animals, and that it directly contributes to coral bleaching (GUNIA‐KRZYŻAK A, et.al. 356. 2018;
SILLER A, et.al 158. 2018.. Currently, its use has been
restricted in coastal areas around the world such as Hawaii, Florida, Indonesia among others, due to its
detrimental effect on coral reefs since these ecosystems are worth between 30-375 billion USD (RAFFA RB,
et al 134. 2019).
Additionally, these restrictions directly compromise the pharmaceutical industry since products with
octinoxate are highly lucrative (RIDDER, M. 2020). Therefore, it has become important to search for less
harmful UV filters
that also offer similar photoprotection properties as those on the market, in order to replace these harmful
molecules without compromising client’s adherence to sunscreen products (LEVINE A. 2020).
Current research has relied on expensive and time-consuming strategies namely biotechnology, SAR studies
and combinatorial chemistry to search for new UV filters
Material e métodos
Development of octinoxate analogs
First, octinoxate analogs were designed using the LAZAR Toxicity Predictions software (MAUNZ A. 4. 2013)
which allowed the
characterization of the analogs’ toxicity profile via LBVS, and the identification of those analogs with a safer
toxicity profile than octinoxate.
Then, in order to choose which analogs to synthesize, a suitable training set (commercial UV filters with an
(E)-cinnamoyl moiety) was first selected from the literature. Next, the structures of the training set and the
analogs were optimized in Avogadro employing the MMFF94s forcefield and the Steepest Descent algorithm
with four steps per update (AVOGADRO. 2018). Afterwards, the PaDEL software was used to calculate 52
molecular
descriptors associated with the absorption capabilities of these molecules (YAP CW. 1466. 2011.
Then, the correlation between the molecular descriptors and molar absorptivities of the training set was
explored using the INQA artificial neural network (GUEVARA-PULIDO J, et al. 7. 2022). The prediction of the
molar absorptivities of the
analogs with safer toxicity profiles was performed after carrying out a systematic analysis to identify the
number of nodes and the number of molecular descriptors that resulted in the best R2 value, the closest to 1.
Analogs that exhibited a safer toxicity profile than octinoxate, and a similar molar absorptivity value
(calculated with an ANN-based prediction model) were the most promising candidates for synthesis.
Synthesis of most promising analogs
Synthesis was accomplished using 2,2,2-trichloro-1,1-dimethylethyl chloroformate as the carboxylic acid
activation agent. Carboxylic acids were activated for 30 minutes using DCM as the reaction medium, and then
the alcohol was added.
Resultado e discussão
We designed 213 novel molecules based on the (E)-cinnamoyl moiety of octinoxate, but only 23 were found
to be less toxic than the parent compound. Then, an ANN-based model was built to predict the molar
absorptivity of those 23 molecules, and the molecule that presented a similar molar absorptivity to that of
octinoxate was chosen for synthesis (analog 4, 3-phenylpropyl (E)-3-(4-methoxyphenyl)acrylate). Synthesis
for analog 4 resulted in a 90% yield, and its photoprotective properties, lipophilicity and cytotoxicity were
evaluated. Analog 4 absorbed UV radiation in the range of 250-340 nm, and it presented a molar absorptivity
of 36155 M-1cm-1. Its lipophilicity resulted in a logkw of 2.49 and its LC50 was greater than that of
octinoxate (67.41 nM vs. 45.67 nM). Therefore, results showed that LBVS is an effective strategy for the
development of new organic UV filters, because it guided the design of less toxic analogs and pinpointed the
most likely analog to exhibit UV properties similar to those of octinoxate. In this case, analog 4 is a promising
alternative to its parent compound since it proved to be more effective and less toxic
Conclusões
Ligand based virtual screening proved to be a useful strategy for designing less ecotoxic octinoxate analogs,
and for guiding the selection of these analogs towards the one that could potentially exhibit similar
photoprotective properties to those of the parent compound. Synthesis of the most promising analog was
supported by H1-NMR and C13-NMR spectra, and the physicochemical and biological assays performed
showed that the analog presented a greater molar absorptivity than octinoxate (36155 M-1cm-1 vs. 23300 M-
1cm-1) and a similar absorbance loss (2.0% vs. 1.0%).
Agradecimentos
This project was funded by INQA Research Group associated to the Pharmaceutical Chemistry Program at
Universidad El Bosque, Bogotá Colombia.
Referências
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