Chemistry Breakthrough Could Lead to Better Drug Design

Lyle Isaacs associate professor, chemistry

Every time you spray an odor-remover like Febreze on a musty carpet, you unleash chemical reactions of aromatic compounds that are carried in neat little protective packets called molecular containers.

While molecular containers occur in nature, those in products like Febreze and pharmaceuticals are synthetic, and don't measure up to the natural version for strength and stability. With molecular containers offering great possibilities in nanotechnology for things like dispensing drugs and medical treatments, scientists have been looking for new ways to create stronger, more stable molecular containers, but have had limited success.

Now, Lyle Isaacs, University of Maryland associate professor of chemistry, and an international research team have made a breakthrough in creating stronger synthetic molecular containers that not only could open new doors for new medical and commercial applications, but can be produced on the scale needed for real world applications.

"This really is a milestone," says Isaacs. "Our results get around some of the big problems encountered in today's synthetic molecular containers and rival those found in nature."

The team's findings were published in the Dec. 17, 2007 online issue of the Proceedings of the National Academies of Science .

Tough Containers

Above: The Isaacs lab created this computer image of a CB[7] Ferrocene molecular container, the blue and red outer circle that contains a molecule (grey interior structure.). How Molecular Containers Work In Febreze: Cyclodextrins form the molecular containers that hold different molecules that produce an aroma. When the molecular containers make contact with that smelly spot, the aroma molecules inside evaporate and release a pleasant smell. The containers continue to work, absorbing the bad smell. In drugs: Many promising pharmaceutical agents cannot become marketed drugs, because they are not soluble in water. Molecular containers come to the rescue by binding the water insoluble drug,enhancing its solubility in water, therefore allowing it to beformulated for consumer use.

Molecular containers are tightly linked rings of atoms that can hold cargo of proteins and other compounds until it's time for the cargo to go into action - to deliver drug therapy, or eliminate odors in a carpet, for example.

"Molecular containers are naturally occurring and important to biology," Isaacs says. "A protein-ligand pair known as Avidin-Biotin is widely used in biological and technological applications because the interaction functions as an irreversible tight glue."

Scientists have developed synthetic molecular containers, called cyclodextrins, which have been successful and important for pharmaceutical and industrial uses. But Isaacs says, they don't match the natural Avidin-Biotin in strength and flexibility. "Cyclodextrins can be leaky. Also, they come in only three sizes, which limits how you can use them.

"Scientists have been trying to come up with synthetic molecular containers that perform the same way as Avidin-Biotin," says Isaacs, "but have had a very hard time because of a general phenomenon known as enthalpy-entropy compensation that is thought to act universally. We found a synthetic host-guest pair that binds as tightly as Avidin-Biotin and does so by overcoming the compensatory enthalpy-entropy relationship."

Stuck Like Glue

That synthetic host-guest pair is called cucurbit[7]uril, or CB[7], a synthetic compound that may be even better than nature's version. "They go so far beyond cyclodextrins. We showed that CB[7] acts as a glue that's very strong but flexible. The CB[7] guest pair is stuck together with the same affinity as the Avidin-Biotin system. CB[7] can be produced in hundreds of grams and it's all done in water, which is much more environmentally friendly."

CB[7] can be produced to accommodate different types of cargo: peptides to modify the body's rate of metabolism; fluorescent molecules to enhance their brightness and extend their lifetime in applications like imaging and lasers; and neurotransmitters for medical diagnosis.

Lyle Isaacs created this 3-D model of a molecular container.

Said Isaacs "Now that we have some of the basic chemistry, we want to try to apply it to all the areas where cyclodextrins are being used. Drug delivery is a big area for cyclodextrins. Water and gas remediation is also a potentially big application."

Simin Liu, a former postdoctoral fellow in the Isaacs lab at Maryland , was also a member of the research team. The research is funded in part by grants from the National Science Foundation.

A chemist through and through, Lyle Isaacs carved the chemical structure of the CB[n] molecule into his Halloween pumpkin. Click here to enlarge photo.

Lyle Isaacs went to college planning to become a doctor. Discovering he wanted to be a chemist instead was an "Aha!" moment for him. "When I took organic chemistry in pre-med, that's when knew I didn't want to be a doctor any more, I wanted to study chemistry. When I was a kid, I had loved playing with Legos, seeing how things fit together. I could envision how things go together chemically. I think of myself as an architect of molecules."

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