The Chiral Quest

By Dana Bauer

ouis Pasteur was just a graduate student when he discovered chirality in 1847. He'd been told to study two acids found in the dregs of wine. Their chemical composition was identical. Yet crystals of tartrate polarized light; crystals of paratartrate didn't.

Under a microscope, every tartrate crystal looked alike. But paratartrate, Pasteur saw, had two forms. One was like tartrate, the other was its mirror image, like a right hand and a left hand. One polarized light clockwise, the other counter-clockwise.Today the fact that chemicals can be right-handed or left-handed is one of the most challenging problems facing pharmaceutical companies. Two thirds of the drugs now on the market — for anxiety, indigestion, heartburn, arthritis, AIDS, and allergies, even the big, billion-dollar drugs like Zoloft — are chiral drugs, which means that of their two forms one is good, the other is ineffective or even dangerous.

The Food and Drug Administration requires chiral drugs to be as pure as possible: as much of the drug as possible should consist of the correct form, or enantiomer. But separating isomers, notes Jason Waldkirch, a graduate student in chemistry at Penn State, is difficult. Isomers have the same physical properties. Same melting point, same boiling point, they dissolve in the same solvents. You have to take a circuitous route to isolate the molecule you want. It's expensive and takes time. "If I'm at a chemical factory making Naproxin, for which the right handed form is useless," Waldkirch says, "I spend my time separating the two — which is difficult — plus I have to dispose of the other half."

A better way is to build only one-handed molecules. Waldkirch's adviser, Xumu Zhang, thinks of it as "precision-making drugs," and he's founded a company, Chiral Quest, to help.

Zhang, an associate professor of chemistry at Penn State, zips around a corner on the third floor of Chandlee Lab and stops short in front of his office door. He has just returned from the headquarters of his company, Chiral Quest, in the Zetachron Center for Science and Technology, Penn State's business incubator about four miles from campus. He flashes a distracted grin in the direction of two graduate students who have been waiting for him, then ushers me into his narrow office, made narrower by the stack of papers and journals on the floor. He opens his laptop to give me a glimpse of the Chiral Quest website, then flips through several dozen sheets of paper on his desk, with drawings of molecules on them, front and back. Zhang is an architect of sorts, a molecular architect: These are ligand designs that he has dreamed, or worked out during the day. "My little daughter looked at all the pictures and said, 'So this is chemistry?'" Zhang laughs.

Zhang's ligands, when linked to a metal ion, create catalysts that not only speed up a chemical reaction or make it more efficient, but force the resulting product into a right-handed or left-handed shape. "Biological activity is associated with absolute molecular configuration," he explains. "You want your catalysts to be rigid. You don't want them to move."

e picks up one of the plastic models from his desk, inch-long tubes in red, blue, and black, that connect to form idealized versions of catalysts. Sometimes he uses computer software to model new designs. "It can help you cut out bad ideas," says Zhang. "But no computer model can tell you what's really going on.

"One of the biggest challenges is not just finding a catalyst that works, but having a clear understanding of the mechanism," he adds. Understanding the mechanism will allow the group to create better catalysts and, ultimately, lower the cost and complexity of making drugs.

"These are our targets," he says, showing me drawings of the molecular structures of the top chiral drugs on the market today: Prilosec, Lipitor, Zocor, Zoloft, Paxil, Vasotec. "When industry gives you a challenging problem, that stimulates your academic work. It works both ways. We're addressing the most fundamental things and the most practical."

The word chiral comes from the Greek chaire, meaning hand. Waldkirch, who as a graduate student teaches introductory organic chemistry courses, holds out both of his hands atop a table. "See my hands. They're the same. Both can turn out the light switch equally well." He jumps up, flicks the fluorescent overhead light on and off. "Both hands can do the same things. Using one hand or the other is not a problem in an 'achiral' environment like this room," he says, waving his hands around the stark chemistry department conference room.

The body, however, is a chiral environment — one in which left- or right-handedness matters. "There are many chiral receptors in the body," says Waldkirch. "Sometimes, the receptor is like a floppy mitten, it's poorly defined and either isomer can fit. Other times the receptor is like a lady's glove — the molecule has to be a tight, exact fit." Occasionally, Waldkirch adds, both isomers have receptors in the body: He grasps my right hand with his right hand, and my left hand with his left hand. "They both fit."

The body is tricky though. It can turn a drug that is right-handed into a mixture of right- and left-handed isomers. An infamous example is thalidomide, the cause of horrible birth defects in the 1950s and '60s. One hand treats morning sickness; the other creates birth defects. "The body runs the reaction much like the reactions taking place in the flasks in our lab," says Waldkirch. "Now we can usually predict what happens to the drug in the body. Back then," he adds, "they didn't have the technology to control it."

That technology includes Zhang's ligands. But how do you go from drawings and plastic models to actual chiral drugs? "Chiral chemistry is in its infancy," says Waldkirch. "People have only been doing it for 30 years; that's when the first ligand was invented.

"Our basic reaction," he adds, "is that we add hydrogen. We start with a prechiral molecule, one that has the potential to be either left- or right-handed. Which side we add the hydrogen molecule to will determine whether it will become left or right."

he catalyst controls this hydrogenation reaction. Zhang's ligands are large organic molecules with small centers and long arms. The arms, which are not quite symmetrical, bond to the prechiral substrate in many places and hold it steady, presenting either its right side or its left to the hydrogen molecule. Because of this multiple bonding, there's no such thing as a universal, "one-size-fits-all" ligand. Each needs to be designed to fit its target. A metal, such as rhodium, palladium, iridium, or ruthenium completes the catalyst. "Without the metal-ligand complex, the substrate would never react with the hydrogen," Waldkirch says. Sometimes the product of this reaction — the hydrogenated substrate — is the desired chiral drug. Other times, it is a few steps away from the drug.

Along with those that catalyze hydrogenation reactions, some of Zhang's ligands work by creating carbon-carbon bonds. In each case, after the reaction is complete, the catalyst detaches and can be used over and over again. Each use is one turnover. Some metal-ligand complexes are good for 1,000, 10,000, and up to 1,000,000 turnovers, depending on the ligand.

In 1998, Zhang licensed his first generation of chiral ligands to a California company called Catalytica . That technology involved three ligands and a series of patents. Catalytica was later acquired by DSM, one of the top five fine chemical companies in the world.

With his second set of eight ligands, Zhang decided to start his own company — Chiral Quest. "The objective is to get to the point where the technology is totally transferable," says Tim Hurley, the president of Chiral Quest. Hurley, dressed smartly in a green polo shirt and khakis, stands in the conference room at the Zetachron Center, where, judging from the extent of the coffee stains on the chairs, many caffeine-inspired discussions have taken place. At the Zetachron Center, University-linked start-ups like Chiral Quest receive the resources they need to grow into self-sufficient companies.

Chiral Quest sells a "toolbox" of six ligands that, when combined with transition metals, can catalyze a variety of reactions, efficiently creating chiral products. The company also offers a screening service for makers of pharmaceuticals and other chiral chemicals that draws on a "library" of more than a dozen ligands Zhang and his graduate students have designed.

Says Waldkirch, "We make new ligands, test them for reactions, and see if they work. We've had a lot of super results." The best are sent on to Chiral Quest. "The ligands look good on paper, and they work well in the lab, but until someone takes them out there to use for a drug, it's just an intellectual pursuit," Waldkirch explains. "Xumu's philosophy is, 'Get the ligands out there for people to use, and it will yield dividends intellectually and financially.' That's part of the reason why the company was created — to make the technology available for people to try to make the next AIDS drug."

Waldkirch is quick to clarify. "We don't make the drugs. We focus on this one step of the process — a transformation that can be used to set chirality. The catalysts we're designing would only affect one step of the drug manufacturing process. The process may have eight or nine steps. But, setting the chirality is the most important step for getting the drug to work well."

Xumu Zhang, Ph.D., is associate professor of chemistry in the Eberly College of Science, 152 Davey Lab, University Park PA 16802; 814-865-4221; xxz6@psu.edu. Jason Waldkirch is a graduate student in chemistry; jpw8@psu.edu. Tim Hurley is president of Chiral Quest; 234-2348; thurley@chiralquest.com. Additional reporting by Nancy Marie Brown.

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