Lab mimics molecule found in poppies
Undergraduate leads synthesis of scarce extract, possible drug precursor


Date:
November 15, 2021
Source:
Rice University
Summary:
An undergraduate leads the discovery of a way to synthesize a rare
molecule drawn from poppies. The molecule could become a building
block for painkillers and other drugs.



FULL STORY ==========================================================================
A Rice University undergraduate student's grit and talent paid off in a
big way when she introduced the first synthesis of a rare and potentially potent molecule drawn from poppies.


========================================================================== Anavi Serna, a junior, spent the duration of a summer fellowship in
the Rice lab of synthetic chemist La'szlo' Ku"rtichasing a sequence
that would produce setigerumine I, an alkaloid molecule found in trace
amounts in the poppy family Papaveraceae.

That natural setigerumine is a molecule the researchers described
as "obscure and elusive," and so hard to isolate it's difficult for
labs to study the molecule as a possible precursor for drugs or other
products. But it was an apt target for Ku"rti's lab, which develops or simplifies chemical paths for the synthesis of pharmaceutical building
blocks used in drug design and manufacture.

Ultimately, Serna and her mentor, Rice chemistry lecturer and
corresponding author Juha Siitonen, produced the natural product in a three-step, room temperature process that started with oxidizing and rearranging a precursor molecule, noscapine, found in cough syrup.

Siitonen, who will become an assistant professor of organic chemistry
at Aalto University in his native Finland in January, had been looking
at setigerumine I, first isolated in 1993, and several other rare poppy extracts for a while.

"Because this molecule is isolated from poppies that also produce
morphine, the likelihood that it has desirable biological properties
is pretty significant," Siitonen said. "We've been facing an opioid
crisis for years now, so we clearly need better painkillers that are non-addictive. We don't know if this is the one, because we've only
just made it, but it might prove practical." The team's paper appears
in the journal Angewandte Chemie.



========================================================================== Serna said her first exposure to synthetic chemistry came in Ku"rti's
class, co-taught by Siitonen. "I had a brief introduction to organic
chemistry in high school, and I didn't like it," she said. "It was all memorizing reactions and the products, and I didn't really understand why things were happening. It wasn't until I took this course that it started making more sense." Siitonen quickly saw her potential. "I showed the molecular structure to her and she said, 'Oh, that's complicated,'" he recalled. "But she wasn't deterred." "Juha did what we should always do
with talented students: Give them a challenge," added Ku"rti. "It took
her less than half the summer to basically get the key results." That
was followed by verification of the results that involved obtaining the molecule's structure through nuclear magnetic resonance spectroscopy.

Siitonen compared synthetic chemistry to solving a Sudoku puzzle, though
with more significant consequences. "We want to understand these chemical puzzles and see how the molecules should be made," Siitonen said. "And
because this molecule exists in nature, that it's a real thing, we know
it must be possible to synthesize." After a lot of trial and error,
the solution turned out to be relatively simple. Their environmentally
friendly process produced 20 milligrams of setigerumine I, enough to
serve as a proof-of-concept for the synthesis.



==========================================================================
"We were very happy, because we didn't expect it would form so readily,"
Serna said. "It was a really nice surprise." "We basically showed
that noscapine and setigerumine I are chemically connected," Siitonen
said. "If somebody wants to produce setigerumine I, our process can
now be further optimized." He noted the process taught the researchers
about how poppies produce setigerumine I. "We also managed to indirectly
prove how this thing actually comes about in nature, which has a lot
of implications," he said. "That includes the fact that it might not be
the only natural product that belongs to this family.

"There might be plenty of these types of molecules in nature with the
same structural motif that we just haven't stumbled across yet," he said.

Ku"rti is a Rice professor of chemistry. Siitonen is a Rice chemistry
lecturer.

The Osk. Huttunen Foundation, a Zevi and Bertha Salsburg Memorial
Fellowship, the National Science Foundation (2102462), the National
Institutes of Health (R35 GM-136373) and the Robert A. Welch Foundation (C-1764) supported the research.

========================================================================== Story Source: Materials provided by Rice_University. Original written
by Mike Williams. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ana Victoria Serna, La'szlo' Ku"rti, Juha Henrik Siitonen. Synthesis
of
(+/-)‐Setigerumine I: Biosynthetic Origins of the Elusive
Racemic Papaveraceae Isoxazolidine Alkaloids. Angewandte Chemie
International Edition, 2021; DOI: 10.1002/anie.202111049 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211115123509.htm

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