COLLEGE STATION --
Texas A&M University scientists are developing a new cancer drug based on landomycin, a natural antibiotic.
In 1990, scientists showed that landomycin has anti-tumor properties, but subsequent laboratory work revealed it was also toxic, which prevented its use as a cancer drug.
"Like a lot of drugs, landomycin did well in cell cultures," says Gary A. Sulikowski, a Texas A&M professor of chemistry, "but when it was given to laboratory animals, it was either too toxic or it got metabolized too fast."
In 1995 Sulikowski decided to synthesize the molecule. By changing its structure, he hoped to make a synthetic cancer drug than would be less toxic than its natural counterpart. Though the synthesis is not yet completed, a large part of the molecule is now finished.
Landomycin is made of a series of six aligned sugars - ring-shaped molecules - and a honeycomb-shaped structure, the "warhead." The first step of the synthesis, which involves making the chain of sugars, has been recently finished. The second step, which consists of building the warhead and attaching it to the sugars, is now under study.
Aligning six sugars is not as simple as it may seem. Indeed, it required years of effort, ingenuity and patience from Sulikowski and his collaborators. To start with, unlike DNA or protein synthesis, sugar synthesis cannot be performed by using an automated machine. Second, linking sugars can be done in many different ways, leading each time to a different compound.
"Even two sugars are complicated to put together because of the many ways they can attach to each other," says Sulikowski. "Not only can they attach at different points, but they can also attach with different spatial arrangements."
Sulikowski and his collaborators tried different chemical reactions to combine two sugars, then three sugars together. The scientists came up with between 15 to 20 reactions to attach the three sugars together. After each reaction, they painstakingly identified the structure of the final compound before moving to the next reaction.
"Running the reactions is probably the simplest part," Sulikowski says. "The hardest part is the structure identification. After each reaction, you have to identify the compound by recording its NMR spectrum as well as its infrared spectrum, optical rotation spectrum and high resolution mass spectrum."
When one of the 15 to 20 reactions failed, the scientists had to redo the latest reaction. But if they ran out of the advanced synthetic intermediate to run the reaction, they had to run all the reactions from the beginning. When the scientists were deep into the synthesis, running a whole chain of reactions anew became more time-consuming and required a great deal of perseverance.
"A lot of people do not realize that when scientists present results in the [specialized] literature, they only tell the good news," says Sulikowski, "but during the course of the work, there are a lot of other failed routes. A reaction that can take a few days to run may have taken six months to find because of all the other reactions that failed."
When chains of three sugars were finally produced, Sulikowski and his collaborators combined them to make the whole 6-sugar chain of landomycin. With up to 25 milligrams of each 3-sugar chain, only three attempts to couple these fragments were possible. Unfortunately, even these reactions failed, and the scientists had to go all the way to the starting point.
The recent synthesis of the 6-sugar chain of landomycin is the culmination of these efforts. Though the entire landomycin molecule is not completed yet, Sulikowski is trying to extend the 6-sugar chain by linking it to an additional 3-sugar chain.
Extended sugar chains have been shown to be more reactive than small ones, Sulikowski says. So the 9-sugar chain may bring the first clues on how to improve landomycin anti-tumor effects.
Sulikowski has recently devised a new way to attach many sugars in one step, the "one-pot method," which promises to reduce scientists' time and efforts and radically improve the synthesis of landomycin.
"This is probably the most exciting prospect for landomycin synthesis," says Sulikowski. "By tuning their reactivity, we can now put several sugars together in one pot and attach them together at one time."
Sulikowski's work is one of 17 projects at Texas A&M receiving a combined $2.94 million from The Welch Foundation, one of the nation's oldest and largest sources for basic chemistry research.
Contact: Gary A. Sulikowski, (979) 845-5746 or email@example.com.