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Researchers Synthesize Rare Anti-Leukemia Compound

April 19, 2009

Some 14 years ago, a family of biological compounds found in sponges in the South Pacific was shown to have very promising effects in fighting leukemia.  Further studies have been stifled for years however by the scarcity of the substance.

But a group of researchers at the Scripps Research Institute has recently discovered a way to circumvent this problem.

Using a few basic amino acids, acetylene gas and a tremendous bit of ingenuity, the research team has developed a technique for synthesizing the chemicals known as kapakahines in large quantities in a laboratory.  More than a decade after the discovery of these promising compounds, further research can now resume at a normal pace, unhindered by product shortages.

The group published its research on the subject in the April 17th edition of the Journal of the American Chemical Society.

To the layman, C. olemda looks like a typical, inconsequential tube sponge; the type you find abundantly inhabiting tropical regions around the world.  For the initiated researcher however, this species of sponge, first discovered in 1995, belongs to a class of marine invertebrates that may contain within its flaccid body the secret to fighting one of the most pernicious forms of cancer.

Each C. olembda produces only a tiny amount of a substance known as kapakahine B.  The potentially leukemia-fighting substance is named after the Hawaiian word for “Ëœtwisted’, a reference to its unique chemical structure that first captured the attention of researchers.

Because each sponge produces such a minute quantity of the curious compounds, researchers had previously been at a loss in trying to find a sustainable means of harvesting them in the quantities required for laboratory investigation.  The ability to synthesize the chemicals in lab would have solved the problem but had previously proved challenging because of the compounds’ extremely unusual structure.

“Chemists are always attracted to things that are bizarre,” said Phil Baran, a chemist at Scripps Research and the leader of the research team.  “There is no shortage of biologists who want to look at active [kapakahine] molecules, but if you can’t provide the molecule, then they can’t go very far.”

Teams of researchers around the world have labored unsuccessfully in recent years to invent a technique for synthesizing kapakahines.  The team at Scripps Research began tackling the problem by first developing a method to synthesize a simpler but related compound know as psychotrimine.  Baran and Tim Newhouse, a graduate student at the institute, published a paper last year in which they described their technique for efficiently synthesizing psychotrimine, a complex alkaloid originally isolated from rainforest bush.

THE FINE ART OF CHEMICAL SYNTHESIS

Newhouse’s synthesis method depended on first creating a highly reactive chemical component known as a quaternary center.  Because of structural homologies, these quaternary centers also make possible the essential first step in kapakahine synthesis.  Baran and Newhouse then worked with postdoctoral researcher Chad Lewis for the even more tenuous second step in kapakahine creation.

Carefully analyzing the structure of kapakahine molecules, Baran’s group correctly predicted that they could use their quaternary center to produce two intermediate isomers; molecules that have identical chemical formulas but different structures.  They predicted that the first isomer would be relatively easy to create, but would not be useful in the creation kapakahines.  The second isomer, though present in much smaller quantities, could serve as an ideal intermediate on the pathway to kapakahine production.  As the chemical reaction moved toward equilibrium, however, they predicted that the concentration of the useful isomer would increase relative to the first isomer.

The risk of this endeavor was that the team would have to invest a tremendous amount of time and energy into investigating whether the isomers would behave as they expected.  If the not, their research would hit a dead end and they would have to start over essentially from square one.

“It was a bit of a dare because this was just a paper idea,” said Baran.  “It was the kind of thing that we knew would be shocking if it actually worked.”

Luckily, their predictions were spot on, and with the most critical step synthesis figured out they were soon producing large quantities of kapakahines for use in leukemia research.

Interestingly, kapakahine B has demonstrated potential in destroying leukemia cells, while a nearly identical compound, kapakahine F, shows no such activity.  The two chemicals differ only by a single amino acid.

Because of the unique structure of kapakahine B, researchers suspect that it may employ a novel mechanism in fighting against leukemia cells, which they hope will open doors in research for the treatment of leukemia.

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On The Net:

Scripps Research Institute

Journal of the American Chemical Society




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