An intricate molecule with exciting anticancer properties that is found only in minute amounts in a few species of South Pacific sponges has for the first time been synthesized in the laboratory by UIC chemists. The 50-step, atom-by-atom assembly, reported in the Nov. 8 issue of the Journal of the American Chemical Society, not only means that scientists will have greater quantities of the rare molecule to study but also points the way to the synthesis of variants that may be even more medicinally useful.
The compound, laulimalide, named from the Hawaiian word laulima, "to work together," attacks cancer cells in a manner similar to the successful cancer drug Taxol but appears to be far more potent against tumors that have developed multiple-drug resistance. Discovered more than 10 years ago, laulimalide, which is chemically unrelated to Taxol, has been studied in several laboratories but is hard to come by, amounting to only one-tenth of 1 percent of a sponge's weight. It has also proven very difficult to make in the lab.
"The molecule is a most challenging one in its structural complexity," says Arun Ghosh, professor of chemistry at UIC. He and graduate student Yong Wang were racing as many as 10 top teams worldwide to synthesize the molecule, whose structure contains a 20-membered ring and nine asymmetric carbon atoms whose "handedness," or stereochemistry must be maintained.
"Building a molecule in a flask with all the bonds and specific configurations found in nature is as hard as building a space shuttle," Ghosh said. "We needed to preserve the stereochemistry at nine centers, maintain the cis configuration of six olefin bonds, and protect the epoxide and ester functions of the molecule."
Most exciting, Ghosh said, is that the stepwise synthesis allows for total control of the handedness of each of the nine asymmetric centers. "We now have the ability to invert each of them, and test each of those molecules for enhanced antitumor activity," he said, making a total of 512 possible variants.
Both Taxol and laulimalide work by disrupting the function of the cellular microtubules required for cell division, but laulimalide also inhibits the P-glycoprotein that is responsible for multiple-drug resistance in those tumor cells that possess it. Although laulimalide is only one-fifth as potent as Taxol in drug-sensitive laboratory cell lines, it is as much as 100 times more potent than Taxol in multi-drug-resistant cell lines.
The research reported in JACS was funded by the National Institute of General Medical Sciences, one of the National Institutes of Health.
Materials provided by University Of Illinois At Chicago. Note: Content may be edited for style and length.
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