Chemists find a quick way to synthesize novel neuroactive compounds
found in rainforest tree
Bark of Galbulimima belgraveana contains compounds that could be the
basis for new psychiatric and neurological drugs

Date:
March 17, 2022
Source:
Scripps Research Institute
Summary:
A potential cornucopia of neuroactive compounds, which might yield
clues to the design of future psychiatric and neurological drugs,
has become more accessible to synthetic chemists.



FULL STORY ==========================================================================
A potential cornucopia of neuroactive compounds, which might yield
clues to the design of future psychiatric and neurological drugs, has
become more accessible to synthetic chemists, thanks to new work from
Scripps Research.


==========================================================================
The discovery, reported March 17, 2022, in Science, concerns compounds contained in the rainforest tree Galbulimima belgraveana and its close
cousin Galbulimima baccata,which are native to Papua New Guinea, tropical northern Australia, and Malaysia.

Potions made from the bark of these trees have long been known to have hallucinogenic and other neuroactive effects, but the precise compounds involved, and their biological targets, have largely been a mystery. The Scripps Research chemists found what is essentially the first streamlined, practical method for synthesizing many of these compounds.

"We're very interested in learning how these Galbulimima compounds affect
the brain, and hope to derive useful new therapeutics from them. Now
with this improved approach to making these molecules, we can start
to do just that," says Ryan Shenvi, PhD, the professor of chemistry at
Scripps Research who led the study.

The co-first authors of the study were Eleanor Landwehr, Meghan Baker PhD,
and Takuya Oguma PhD, who worked in the Shenvi lab during the study.

The neuroactive effects of compounds found in Galbulimimabark were
first highlighted just after World War II in surveys by the pharma
company Smith, Kline & French and the Australian national research
organization CSIRO. Until now, though, the dense structural complexity
of these compounds, their variable mix within Galbulimimabark, and the difficulty of obtaining that bark in quantity, have prevented their close study. Indeed, chemists had devised a concise and practical synthesis
for only one of these compounds, himbacine.

In the new study, Shenvi and his team targeted another Galbulimimacompound called himgaline, which, like himbacine, appears to have antispasmodic properties, though it is likely to act in a different way. Whereas
the best prior method to synthesize himgaline requires 19 steps -- too
many for routine use -- the new method took only 7 steps, enabling easy synthesis at the scale needed to study the compound in detail.

Shenvi says the new method is more efficient in part because it starts
with a broad approach to the chemical "space" or "neighborhood" around himgaline, allowing that specific compound -- or other related compounds
-- to be made relatively easily from there. Using this approach, the team demonstrated syntheses of himgaline and two other Galbulimimacompounds,
GB22 and GB13.

"Our approach is somewhat analogous to distant space travel -- we
first try to get to the target star system, so to speak, and from there
it's relatively easy to get to specific planets within that system,"
Shenvi says.

Shenvi and his team are now following up with studies of the biological properties of himgaline, GB22 and GB13, and are also using their broad synthesis strategy to make and study other Galbulimimacompounds.

"Concise syntheses of GB22, GB13, and himgaline by cross-coupling and
complete reduction" was co-authored by Eleanor Landwehr, Meghan Baker,
Takuya Oguma, Hannah Burdge, Takahiro Kawajiri and Ryan Shenvi, who were
all at Scripps Research during the study.

The work was funded in part by the National Institutes of Health
(GM122606) and the National Science Foundation (CHE1856747).


========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Related Multimedia:
*
Breakthrough_chemical_synthesis_of_neuroactive_plant_metabolite_himgaline ========================================================================== Journal Reference:
1. Eleanor M. Landwehr, Meghan A. Baker, Takuya Oguma, Hannah
E. Burdge,
Takahiro Kawajiri, Ryan A. Shenvi. Concise syntheses of GB22, GB13,
and himgaline by cross-coupling and complete reduction. Science,
2022; 375 (6586): 1270 DOI: 10.1126/science.abn8343 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220317143751.htm

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