Novel synthetic process for the core structure of the fungal antiviral
agent neoechinulin B and its derivatives
Date:
February 9, 2022
Source:
Tokyo University of Science
Summary:
The fungus-derived compound neoechinulin B demonstrates promising
antiviral activity. To realize its potential as an antiviral agent,
however, a viable method for preparing more potent derivatives
synthetically is necessary. In a recent breakthrough, scientists
from Japan designed a simple route for synthesizing neoechinulin B
and its derivatives under mild laboratory conditions. Neoechinulin
B and six derivatives exhibited excellent antiviral activities
against hepatitis C virus and SARS-CoV-2, the virus responsible
for the COVID-19 pandemic.
FULL STORY ==========================================================================
The solutions to many of humanity's problems can be found within
nature. For instance, who could have guessed that an antibiotic as
powerful as penicillin would be found in a common mold, or that the drug aspirin would be derived from the bark of the willow tree?
========================================================================== Research into natural products has become a crucial part of drug
discovery.
Natural products have exhibited promising specificity and efficacy when
used against a variety of pathogens, including viruses. For instance, an organic compound called neoechinulin B, isolated from the fungus Eurotium rubrum,has demonstrated antiviral activity against hepatitis C virus
(HCV). However, the isolation of such compounds from natural sources
can get quite tedious and expensive. Yet, the attempts to synthetically synthesize it seem to be very scarce.
Thus, a group of scientists from across Japan rose to the occasion
and embarked on a mission: To discover a simple route for synthesizing neoechinulin B under laboratory conditions. The team included Prof. Kouji Kuramochi and Dr. Koichi Watashi from Tokyo University of Science,
along with Dr. Hirofumi Ohashi, Dr.
Shusuke Tomoshige, Dr. Kenji Ohgane, and Dr. Shinji Kamisuki from the
National Institute of Infectious Diseases, Tohoku University, Ochanomizu University, and Azabu University, respectively. Their findings were
recently published in the Journal of Natural Products.
Commenting on their strategy, Prof. Kuramochi, the lead author of the
study, says: "We designed a streamlined two-step synthesis strategy to
obtain diketopiperazine scaffold of neoechinulin B. The process involved
the base- induced coupling of available piperazine-2,5-dione derivative
was aldehydes.
The coupled products were then treated with a commercial reagent called
tetra- n-butylammonium fluoride (TBAF) which gave us neoechinulin
B and its 16 other derivatives." To ascertain the efficacy of their
products, the team tested the antiviral activity of neoechinulin B and its derivatives against different positive- strand RNA viruses, such as HCV
and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). They
found that some derivatives showed anti-HCV activity with minimal cell toxicity, while others showed anti-SARS-CoV-2.
Moreover, six derivatives exhibited both strong anti-HCV and SARS-CoV-2.
Further studies by the research team uncovered that neoechinulin
B and one derivative can reduced the transcriptional activity of
liver X receptors (LXRs). This subsequently disrupts the formation of double-membrane vesicles (DMV), which are the sites where viral RNA
replication occur. This process results in reduced viral replication in
the infected cells.
Along with the 17 active compounds, the scientists also produced
three other compounds which, while structurally related to the others, possessed none of the antiviral properties. Further investigation into
their molecular structure revealed that inactive compounds were missing
the exomethylene moiety which is the key to the antiviral activities of neoechinulin B and its 16 derivatives against HCV and SARS-CoV-2.
The team believes that the insights from this research could be used as a framework for the development of new broad-spectrum antiviral drugs. The
study also solidifies the fact that natural products can act as promising
lead compounds for the development of antiviral drugs. "The skeleton of neoechinulin B is simple, but only one chemical synthesis method has
been reported in the past. Our research presented a simple and viable
method for obtaining promising antiviral compounds bringing us one step
closer to its practical application," concludes Prof. Kuramochi.
========================================================================== Story Source: Materials provided by Tokyo_University_of_Science. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Kota Nishiuchi, Hirofumi Ohashi, Kazane Nishioka, Masako Yamasaki,
Masateru Furuta, Takumi Mashiko, Shusuke Tomoshige,
Kenji Ohgane, Shinji Kamisuki, Koichi Watashi, Kouji
Kuramochi. Synthesis and Antiviral Activities of Neoechinulin B
and Its Derivatives. Journal of Natural Products, 2021; 85 (1):
284 DOI: 10.1021/acs.jnatprod.1c01120 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/02/220209112123.htm
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