In early 2007, Northwestern University chemist Karl Scheidt's interest was piqued when marine chemist Amy Wright reported in the Journal of Natural Products that a new natural compound derived from an uncommon deep-sea sponge was extremely effective at inhibiting cancer cell growth.
As a synthetic chemist fascinated by natural products and their potential in medicine, Scheidt knew what he had to do: Make that molecule.
After six months of intense effort, Scheidt, graduate student Daniel Custar and postdoctoral fellow Thomas Zabawa successfully built the molecular structure reported in the paper. That's when they discovered something strange and unexpected when they compared the spectra, or unique molecular fingerprints, of their structure and that of the natural compound: The spectra did not match, which meant that the structures did not match. Something was wrong.
This story and how the Northwestern team solved the mystery and determined the real structure of neopeltolide, the natural compound derived from the marine sponge, is reported in a paper published in the Jan. 23 issue of the Journal of the American Chemical Society (JACS). Knowing neopeltolide's structure will help researchers learn how the new compound works, which could lead to new, more-effective anti-cancer drugs.
“The reported biological activity of this new natural compound was fantastic -- two to three orders of magnitude more potent for some cancer cells than Taxol®, a common chemotherapy drug,” said Scheidt, assistant professor of chemistry in the Weinberg College of Arts and Sciences at Northwestern. (Taxol® also has its origins in nature, having been extracted from the Pacific yew tree.) “Synthetic chemists are inspired by such structures. Because of the potential benefits to human health, these are the compounds you want to go after.”
Marine sponges can't move and escape predators, and they don't have claws, teeth or quills, so they have developed a different kind of defense mechanism: chemical protection. The sponge and/or bacteria hosted by the sponge produce poisonous compounds to ward off enemies. This chemical factory makes sponges rich sources of interesting natural products, many with cell-killing abilities.
After discovering the spectrum of their first built molecule did not match the natural compound's spectrum, Scheidt and his team faced two possibilities -- either they had done something wrong while building the molecule or the structure was reported incorrectly.
The researchers double checked their methods, found they were “spot on” and concluded the structure was reported incorrectly. Which meant the right structure still needed to be determined. Custar and Zabawa decided to set up a cot in the lab's computer room to cut down on their commute to the lab and set to work.
Again, using simple starting materials and complex chemical synthesis, the team built a new molecule, just slightly different from the first one. This time they perturbed just two carbon atoms, making them “down” instead of “up,” in chemist speak. The researchers compared the spectrum of this new structure with that of the natural compound, and this time the spectra matched perfectly. These results are those published in the JACS article.
To construct the compound, Scheidt, Custar and Zabawa used an efficient, convergent synthesis, a bit akin to how a car is put together on an assembly line -- with major parts, like the engine, built separately and then put together in the final piece. “Our approach brings three equal fragments together to form the whole, which is better than building in a linear sequence,” said Scheidt. “We pushed the envelope of what can be done with organic chemistry to do it.”