Big discoveries are rare in research labs. Most of the time, scientists have to try over and over again to achieve the effect they want. Drugs are especially tricky, since even effective drugs can have toxic side effects. Fiddling with the molecular structure can improve a drug—or make it worse. Up until now, those attempts to tweak existing drugs focused on the carbon chemistry of medicine. Like humans, medicines are made up mostly of carbon.
But the Organosilicon Research Center of UW-Madison seems to have hit gold on its first venture in drug discovery. Acting on a suggestion from a colleague in Arizona, the scientists tried adding silicon to a drug already on the market.
The very first compound they tried not only works better as a painkiller—what the original drug is used for right now—but shows potential for treating pancreatic cancer, one of the deadliest forms of cancer.
The original drug, indomethacin, is a powerful painkiller. Like ibuprofen and other non-steroidal, anti-inflammatory drugs, it steps in at an early stage in the body's production of pain.
Normally, the enzyme named cyclooxygenase-2 (COX-2) sets off a chain of reactions that scream pain to the brain. However, indomethacin blocks the enzyme's active site and keeps the chain reaction from starting. It's like putting blanks in the gun of a trigger-happy rent-a-cop.
But indomethacin does not distinguish between COX-2 and its benign twin, COX-1. Unlike COX-2, which is responsible for pain, COX-1 plays a vital role in making prostaglandins. These molecules safeguard the lining of your stomach and keep your gastrointestinal tract running smoothly. Because indomethacin shuts down production of COX-1, most people using the drug for pain end up with ulcers or internal bleeding.
Powerful drug, major downside. It was a good candidate for the scientists at the Organosilicon Research Center to start with.
The lab obtained silicon to work with by heating sand to 300 degrees and tossing in some methyl chloride to help break it down. Then they tricked the silicon into reacting with a handful of carbons. Finally, they combined it with indomethacin to give the organosilicon compound they've informally named ""silamethacin.""
""The beauty of it was the first compound we tried turned out to be a winner,"" said Robert West, UW-Madison professor of chemistry and head of the research center. ""Luck smiled on us.""
The new compound is a thousand times more selective for COX-2 than indomethacin. This means it leaves COX-1 and valuable prostaglandin production alone, while retaining its painkilling power.
Galina Bikzhanova, the research associate responsible for a lot of the lab work, explained why adding silicon made such a difference.
""It is the size of the active sites,"" Bikzhanova said. ""You look at the COX-1 active site, it's actually a little bit smaller than COX-2. There is amino acid residue which occupies free space. Basically, silamethacin is going to fit only COX-2.""
Furthermore, the silicon helps stabilize the compound. Past attempts to modify indomethacin resulted in drugs that broke down too fast once they were in the body to have any effect. But ""silamethacin"" has such good staying power that West and head researcher Galina Bikzhanova don't know if it will break down. It hasn't yet.
""But that was just the beginning,"" West said. He said indomethacin was known to have some anti-cancer properties. So the lab at RND Pharmaceuticals, an Arizona-based company collaborating with the research center here, tried ""silamethacin"" against four cell lines.
The result? The new compound works spectacularly against pancreatic cancer.
Pancreatic cancer is fourth on the list of deaths caused by cancer, according to David Mahvi, a professor and surgeon in the UW-Madison oncology department. The cancer often spreads to other parts of the body before it is ever diagnosed. But even when it's caught in the early stages and surgically removed, 70 percent of patients have a recurrence of the disease.
Although there are some bright drugs on the horizon, Mahvi said, nothing available right now works well.
""We'd love to find a new drug that works, especially if one was specific,"" Mahvi said.
For now, the compound is still in the early stages of testing. West said it would probably be 10 to 12 years before any drugs come out of the research center's current work. But they will continue to seek ways to improve the compounds they're working on now, as well as try to find other medicines that might benefit from a touch of silicon.
""If what we're doing in our research can help people in the future, that's what drives us,"" Bikzhanova said.
