Scientists from Scripps Research report that they have carried out a study on a number of neuroactive compounds which might yield clues to the design of future psychiatric and neurological drugs. Their research (“Concise syntheses of GB22, GB13, and himgaline by cross-coupling and complete reduction”), which appears 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 believe they have found what is essentially the first streamlined, practical method for synthesizing many of these compounds.

“Neuroactive metabolites from the bark of Galbulimima belgraveana occur in variable distributions among trees and are not easily accessible through chemical synthesis because of elaborate bond networks and dense stereochemistry. Previous syntheses of complex congeners such as himgaline have relied on iterative, stepwise installation of multiple methine stereocenters,” write the investigators.

“We decreased the synthetic burden of himgaline chemical space to nearly one-third of the prior best (7 to 9 versus 19 to 31 steps) by cross-coupling high fraction aromatic building blocks (high Fsp2) followed by complete, stereoselective reduction to high fraction sp3 products (high Fsp3). This short entry into Galbulimima alkaloid space should facilitate extensive chemical exploration and biological interrogation.”

“We’re 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 neuroactive effects of compounds found in Galbulimima bark 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 Galbulimima bark, 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 Galbulimima compound 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 Galbulimima compounds, 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 Galbulimima compounds.

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