Kapakahine B, which has shown potential for fighting leukemia, comes from the tube-type sponge Cripbrochalina olemda. Illustration by Kevin Fung.
"Chemists are always attracted to things that are bizarre," says Phil Baran, a Scripps Research chemist.
In this case, the oddity was kapakahine B, a chemical named after the Hawaiian word "kapakahi" meaning "twisted" because of its unusual structure.
More than a decade ago, researchers found that the compound had leukemia-fighting potential, possibly due to some never-before-seen mechanism behind its unusual structure. But researchers' work was stalled because of the chemical's lack of availability.
Kapakahine B comes from a South Pacific sponge, but each sponge contains only trace quantities. Even if mass quantities of the sponge could be harvested – devastating ocean ecosystems in the process – it would still be difficult to get enough material to work with. And should kapakahine B and its class of related chemicals prove an effective disease treatment, it would likely be impossible to get enough for commercial use.
Baran and his team were too intrigued to give up, though.
"There is no shortage of biologists who want to look at active molecules, but if you can't provide the molecule, they can't go very far," he says.
His team joined the groups of chemists around the world working to devise a method for synthesizing kapakahines in the laboratory.
The Scripps Research team's success began with research to synthesize a simpler related compound that had no known pharmaceutical potential. Tim Newhouse, a graduate student in the Scripps Research Kellogg School of Science and Technology, published a paper last year with Baran that detailed his invention of a simple and highly efficient synthesis of a chemical compound that was originally isolated from a rainforest shrub.
Using the first step of this synthesis process, Newhouse then teamed up with Chad Lewis, a postdoctoral researcher in the Baran lab, to develop a technique that would work for kapakahines.
The team predicted they could use the chemical compound from Newhouse's experiment to produce two intermediate isomers – molecules with the same chemical formula but different structures. One, they predicted, would be easy to make but would not provide a direct chemical pathway to creating kapakahines. The other would be an ideal stepping stone to producing kapakahines, but would be much more difficult to make.
The second isomer would be much more reactive, though, and their theory was that, as it moved toward equilibrium with the first molecule, it would grow in concentration.
"It was a bit of a dare because it was just a paper idea," says Baran. "It was the kind of thing that we knew would be shocking if it actually worked."
And shocked, they were.
The researchers were able to synthesize gram quantities of two kapakahines for the first time. Now, 14 years after they were first discovered, full research into the kapakahines' potential can finally proceed.
Because the kapakahine structure is so unique, there is a good chance that its activity is different from that of other compounds with potential against leukemia – opening the possibility of an entirely new form of treatment.
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