Jan. 27, 2003 In an organic chemistry lab on the campus of Binghamton University in upstate New York, Scott Handy is busy whipping up promising new substances modeled after natural compounds found in sea sponges and tobacco plants.
Some of the synthetic compounds could help in the fight against cancer and AIDS. Others could provide a safer, more effective, and more affordable alternative to the traditional solvents organic chemists use to catalyze reactions and synthesize compounds, one molecule at a time.
A synthetic organic chemist and teacher, Handy clearly gets a charge out of creating and nurturing things, organic and otherwise, a fact underscored by his avocations--which include cooking, gardening and music. But when it comes to his research, even though synthesizing molecules can take years of dedication and no end of patience, experiencing the success of creation is only half the fun, he said.
"For some people, making a molecule is sufficient, and that certainly is enough of a challenge much of the time," he said. "But what I really like about synthesis is that if you can make a molecule, you can make a molecule that you can do something with. And that's what breathes life into things for me. It adds a whole other level of excitement and purpose to my research."
That probably explains as well as anything Handy's interest in synthesizing the lamellarins, a family of naturally occurring compounds derived from marine sponges native to the Indian Ocean. Lamellarins have proven to be deadly, or cytotoxic, to cancer cells. More than that they have shown the ability to kill particular cancer cell lines that are considered multidrug-resistant. Such cell lines are essentially equipped with cancer's version of a bilge pump, Handy said, an enzyme that actively transports most drugs out of the cell before they can take effect. As a result, the cells are resistant to many of the drugs and treatment protocols normally used to combat cancer. Once introduced into multidrug-resistant cancer cells, though, lamellarins act quickly to disable and disrupt the cells' pumps. They are then free to remain in the cells until their work is done, meaning until the cells are killed off by either the lamellarins or another companion drug.
Unfortunately, for all their obvious promise in both the treatment of cancer and AIDS, where they have shown the ability to inhibit HIV integrase and thereby control the disease, lamellarins, like many naturally occurring substances of their ilk, are difficult and expensive to come by. The most obvious problem is that ripping up chunks of coral reef to secure marine sponges is illegal in many places and not a good environmental practice. But even if the marine sponges were readily available, they produce lamellarins in such infinitesimal quantities as to make the prospect of collecting and commercializing their use impractical.
Enter Handy and his research team. After more than two years of work, Handy's group last month successfully synthesized the molecular skeleton of the lamellarins, an accomplishment that will now allow them to begin looking for ways to simplify it, while maintaining or amplifying its desired abilities.
In this process, each new variation of a compound is referred to as an analog, and the process of homing in on the best analog can be a long and exhaustive one, Handy said. The pharmaceutical industry, for instance, expects to make about 100,000 analogs before arriving at a compound they can actually take to clinical trials. This is the phase Handy refers to as the "Lego" approach.
"That's the stage where we start taking the compound apart and asking 'What happens if we stick the different parts together in a mix and match way," he said. "Now that we have the whole skeleton figured out, we can put it together however we want."
That will allow Handy and his team to begin teasing the compound apart so that they can better isolate those parts of it that provide the desired activities...in this case cytotoxicity, inhibition of HIV integrase, or interaction with tubulin. A protein that is key to cell replication, tubulin is critical in the progression of many cancers. There the normal cell replication process is hijacked and ramped up to a much higher than normal rate. Compounds that interfere with tubulin, however, can bring cell replication to a screeching halt, essentially arresting cancer in its tracks. Robbed of the ability to replicate, cancer cells eventually die. Another Binghamton University researcher, Susan Bane is an expert on tubulin, and Handy is working with her to explore the interaction of lamellarins and tubulin.
Synthetic organic chemists might begin their work by dumping scoops of materials into large flasks, Handy said. But when all is said and done-sometimes after 10, 15 or even 20 reactions and, if the compound is complex, two or more years later- they might well be left with an end product that has to be measured at the milligram level, barely visible to the human eye.
The "Lego" approach then allows chemists to find ways to produce an effective substance more easily, more rapidly and, more cost effectively. Handy is also working to make sure that organic synthesis can be accomplished more safely.
Key to almost every organic synthesis are substances known as reaction solvents. Normally toxic, flammable, highly volatile and petroleum based, these are the substances that dissolve all of the different molecules that are going to react and form the new product molecule and help this reaction to proceed efficiently. They can be costly to work with and because of their toxicity even more costly to dispose of, something that needs to be done with troubling regularity.
Handy is developing nicotine-based reaction solvents that seem to have none of the drawbacks of traditional solvents and that are proving their ability to actually catalyze and facilitate certain types of reactions that traditional solvents do not, Handy said. "Building these things out of a biorenewable resource, no longer based on petroleum is a big selling point," Handy said. "But even more than that these are recycable systems, so you can use the solvent over and over and over and over."
After being tipped off to a possible connection by the sponsored funding database, Community of Science, Handy said his work has attracted some interest from Philip Morris Inc., which is seeking applications for tobacco and nicotine in a variety of areas including the environmental sciences.
Handy credits his use of Community of Science, a $10,000 per year resource the University provides free to all its faculty members, for keeping his research moving forward. In an increasingly competitive sponsored funds environment, young and even mid-career researchers often can't realistically expect to succeed with proposals to the National Institutes of Health or the National Science Foundation on their first or even second go round, he said.
"Trying to find other agencies isn't always easy, but COS is really helpful for this," he said, "and the smaller agencies often have more niche opportunities that can give you a competitive advantage."
Handy's current research, for instance, is partially supported by a $75,000 grant from the Leukemia Research Foundation, an opportunity he learned about on COS. With the right degree of commitment and enterprise Handy has discovered, opportunity can be created about as readily as most anything else.
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