Scientists invent first technique for producing promising anti-leukemia agent

Apr 17, 2009

Kapakahines, marine-derived natural products isolated from a South Pacific sponge in trace quantities, have shown anti-leukemia potential, but studies have been all but stalled by kapakahines' lack of availability.

But using only acetylene gas, a handful of amino acids, and a dozen inventive steps, a team from The Scripps Research Institute has finally established the first technique to synthesize kapakahines in the laboratory in large quantities, more than a decade after their discovery. With supplies now in hand, and unlimited production potential established, research on the compound can proceed and may eventually lead to new drug treatments.

The research is described in a paper published online by the on April 17, 2009.

Cripbrochalina olemda appears to the uninitiated as a common tube-type sponge similar to countless others you might find on reefs throughout the tropics. But this species, discovered in 1995, is one of a growing number of researchers have found that naturally produce chemicals with great potential for fighting diseases such as cancer.

C. olemda produces a compound called kapakahine B, among other of interest, that has shown potential for fighting . As important, kapakahine B, named after the Hawaiian word kapakahi, which means "twisted," has an unusual structure that researchers had never seen before, suggesting that its ability to fight may stem from some never-before-seen mechanism.

The problem is that amassing enough of the kapakahines to conduct full studies had proven an untenable proposition. Each sponge contains only a relative speck of the compounds. Even if massive 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 would likely be impossible to get enough for commercial use should a kapakahine prove an effective disease treatment. Being able to synthesize the compounds in the lab would solve the problem, but this has proven challenging.

"Chemists are always attracted to things that are bizarre," says Phil Baran, a Scripps Research chemist and leader of the group, of the kapakahines' strange twists. While at times that can be enough motivation for research, in this case, the attraction is deeper. "There is no shortage of biologists who want to look at active molecules, but if you can't provide the molecule, then they can't go very far."

Groups of chemists around the world have endeavored unsuccessfully to devise a method for synthesizing the kapakahines. The Scripps Research team's success with the challenge began with more basic research to synthesize a simpler related compound with no known pharmaceutical potential. Tim Newhouse, a graduate student in the Scripps Research Kellogg School of Science and Technology, last year published with Baran a paper detailing his invention of a simple and highly efficient synthesis of a complex alkaloid called psychotrimine, which was originally isolated from a rainforest shrub.

Risky Chemistry

The Newhouse synthesis hinged on the creation of a highly reactive and selective chemical component referred to as a quaternary center that, because of structural similarities, also drives the essential first step in the kapakahines synthesis. Chad Lewis, a postdoctoral researcher in the Baran lab, then teamed up with Newhouse to set out on a somewhat riskier venture to develop a second stage needed to synthesize kapakahines.

On paper, by analyzing and deconstructing the kapakines' structure, the Baran group predicted that using the quaternary center they could produce two intermediate isomers, or molecules with the same chemical formula but different structures. One isomer, they predicted, would be easy to make, but would be a divergence from the chemical pathway to the kapakahines. The other would be an ideal stepping stone toward the kapakahines, but more difficult to make, meaning in this case only the smallest of quantities would be produced relative to the first isomer. But the second isomer would be much more reactive, and in theory its concentration would grow sufficiently as it moved toward equilibrium with the first isomer.

The risk was that substantial work was required to discover whether the isomers would behave as predicted, allowing the synthesis to proceed. If they didn't, all the work would have led to a dead end. "It was a bit of a dare because this was just a paper idea," says Baran, "It was the kind of thing that we knew would be shocking if it actually worked."

The researchers' predictions did ultimately prove correct, allowing them to synthesize two kapakahines for the first time and in gram quantities. That means that now, some 14 years after they were discovered, full research into the kapakahines' potential can finally proceed.

One of the compounds, kapakahine B, has shown potential in fighting leukemia cells. Interestingly, the second, kapakahine F, which has a very similar structure, shows no such activity. The only difference between the two is the addition on B of a single amino acid residue.

Having this critical component already identified should simplify studies of kapakahine B's anti-leukemia activity, an essential step in research on any potential drug treatment. And, because the kapakahine structure is novel, there is a good chance that this activity is different from that seen in other compounds with potential against leukemia, opening the possibility of an entirely new form of treatment.

Another tantalizing prospect is that the relatively inactive kapakahine F could be easily manipulated to form a library of new compounds by adding different chemical groups to the reactive spot where phenylalanine leads to kapakahine B's activity, and these analogs could proven even better at fighting leukemia or other forms of cancer than B.

More information: The study, authored by Newhouse, Lewis, and Baran of Scripps Research, is titled "Enantiospecific Total Syntheses of Kapakahines B and F." For more information, see pubs.acs.org/doi/abs/10.1021/ja901573x

Source: The Scripps Research Institute (news : web)

Explore further: Cells build 'cupboards' to store metals

add to favorites email to friend print save as pdf

Related Stories

Chemists synthesize herbal alkaloid

Apr 15, 2009

The club moss Lycopodium serratum is a creeping, flowerless plant used in homeopathic medicine to treat a wide variety of ailments. It contains a potent brew of alkaloids that have attracted considerable scient ...

New method enables design, production of extremely novel drugs

Jan 23, 2008

A new chemical synthesis method based on a catalyst worth many times the price of gold and providing a far more efficient and economical method than traditional ones for designing and manufacturing extremely novel pharmaceutical ...

Periwinkle can serve as tiny chemical plant

Nov 16, 2006

MIT researchers have discovered a way to manipulate the chemistry taking place in the tiny periwinkle plant to produce novel compounds that could have pharmacological benefits.

Recommended for you

Cells build 'cupboards' to store metals

12 hours ago

Lawrence Livermore researchers in conjunction with collaborators at University of California (link is external), Los Angeles have found that some cells build intracellular compartments that allow the cell ...

Stunning zinc fireworks when egg meets sperm

Dec 15, 2014

Sparks literally fly when a sperm and an egg hit it off. The fertilized mammalian egg releases from its surface billions of zinc atoms in "zinc sparks," one wave after another, a Northwestern University-led ...

User comments : 1

Adjust slider to filter visible comments by rank

Display comments: newest first

LuckyBrandon
not rated yet Apr 18, 2009
If F is merely lacking a certain amino acid, would it not be smarter to just convert type F into type B and NOT spend all kinds of wasted time trying to create new variations. Get something that works with B first, then improve from there. Stop wasting time, people are dying because of it.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.