Promising anti-TB compound finally can be synthesized with ease

February 10, 2005

BUFFALO, N.Y. -- An efficient new strategy for synthesizing a natural marine product, which shows promising anti-tuberculosis activity but cannot be efficiently synthesized using conventional chemistry, is being reported by University at Buffalo organic chemists online on Feb. 10 in Angewandte Chemie International Edition.

The UB researchers' method synthesizes the compound in days rather than months, requires fewer steps and is capable of producing gram quantities.

The UB chemists describe the direct synthesis in the laboratory of the natural product isolated from the Pseudopterogorgia corals. They now are applying the synthesis method to other members of this class of compounds called diterpenes, some of which also have activity against TB and are potential anti-inflammatory and anticancer agents.

"We're poised now to make them all and to develop new analogs as potential medications," said Huw Davies, Ph.D., Larkin Professor of Organic Chemistry at UB and co-author.

Once thought to be nearly eliminated, tuberculosis is again among the world's most-deadly infectious diseases, killing between 2 million and 3 million people each year.

Its reemergence has been triggered partly by AIDS, which makes an individual 30 times more likely to develop TB, and by multidrug resistance caused by difficulties in getting patients to comply with long treatment regimens.

Davies explained that the family of marine compounds called diterpenes was discovered and demonstrated to have anti-TB activity in 2000, but as with most natural products, so little could be extracted from the marine organism that full biological evaluation was not possible.

To circumvent the problem, chemists have concentrated their efforts on producing the compounds in the laboratory.

Davies explained that the compounds have proven remarkably difficult to synthesize not because they're so complex, but because important regions in the molecule lack functional groups to control the chemistry.

Efforts to synthesize the compound using conventional chemistry have required the tedious addition and subsequent removal of functional groups, inefficient and lengthy procedures that Davies noted have resulted in producing only very small amounts of the compound.

In addition, he explained, conventional methods fail to control the synthesis of the desired three-dimensional shape of the natural product, sometimes producing not only the target compound but its mirror image as well, an undesirable outcome for pharmaceutical synthesis since some mirror-image molecules can be dangerous if consumed.

By contrast, the newly developed strategy developed by Davies and Abbas M. Walji, Ph.D., co-author and former doctoral candidate in the UB Department of Chemistry, circumvents the need for functional groups.

At the same time, it allows for the production of only the desired product and not its mirror image.

"It turns out that because of the carbon-hydrogen activation in our process, our chemistry is perfect for this target," said Davies. They do it through the use of a special catalyst Davies developed, which at once catalyzes the activation of the normally unreactive carbon-hydrogen bonds and produces only the target compound.

"We solve the control of the three-dimensional shape all in this one key step," said Davies.

"The synthesis is now so smooth that we are able to complete the whole sequence in only 10 days, a process that with more conventional chemistry easily could take one year," said Davies.

This work expands on previous research by Davies that resulted in extremely efficient methods of producing Ritalin, the treatment for children with attention-deficit disorders, and sertraline, the commonly prescribed antidepressant marketed as Zoloft.
The current research is funded by the National Science Foundation.

University at Buffalo

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