C&EN Washington

One of the first things people notice about Ronald Breslow is how quick his mind is. "He can think through a problem intuitively, somehow, while the rest of us are trying to think it through in our own normal way," says Robert G. Bergman, professor of chemistry at the University of California, Berkeley, and a former postdoctoral fellow in Breslow's laboratory at Columbia University. "He gets to the answer amazingly fast and really understands what's going on."

That speed can take some getting used to. "One of the challenges of carrying on a conversation with Ron is to get to your point quick enough before he fills in all the gaps and gets there before you," says another former postdoc, Larry E. Overman, now professor of chemistry at the University of California, Irvine. Such speed is "not meant to be a put-down in any way," Overman adds. "That's just the pace that he goes."

Breslow impresses those who know him with more than his quickness. Colleagues describe him as someone who pays as much attention to people as he does to chemistry. "I am in awe of the way he has somehow managed to merge a lot of very important personal and human qualities with his chemistry," Bergman says. "In an era when a lot of people tend to look at science and scientists as being very self-serving and self-aggrandizing, Ron is an example of somebody who is not like that. I think he is about as successful as anybody would want to be, yet he doesn't put his own needs in front of other people's."

Says Overman: "He excels in every aspect of what being a professional chemist means. He's done groundbreaking research in many areas. He's an inspiring teacher at the undergraduate, graduate, and postdoctoral level. He's set a standard that very few can keep up to in terms of service to our community and articulating major problems. He's been very concerned about communicating chemistry to the broader community. And while he successfully does all this, he also has a very wonderful family, a delightful wife and children. He balances this all in a most remarkable way."

That high regard doesn't come just from former students. "All of us in the chemical community are beneficiaries of Ron's passion and enthusiasm for chemistry," says Peter B. Dervan, professor of chemistry at California Institute of Technology. "I can recall many American Chemical Society meetings and Gordon Conferences where Breslow in the audience just lifted the entire level of the discussion with the breadth of his intellect." This week, that high regard will be reaffirmed when ACS honors Breslow with its highest award, the Priestley Medal, at a ceremony on March 23 during the society's national meeting in Anaheim, Calif.

Breslow is professor of chemistry and University Professor at Columbia. A member of the National Academy of Sciences and the American Academy of Arts & Sciences, he has received many awards for his research and teaching accomplishments. The former include ACS's Award in Pure Chemistry in 1966, the James Flack Norris Award in Physical Organic Chemistry in 1980, and the Arthur C. Cope Award in 1987; the National Academy of Sciences Award in Chemistry in 1989; and the U.S. National Medal of Science in 1991. Columbia University alumni awarded him their Great Teacher Award in 1981, and the students of the university recognized his teaching skill with the Mark Van Doren Medal in 1969.

Breslow's efforts on behalf of the chemical profession include chairing the Chemistry Division of the National Academy of Sciences from 1974 to 1977, chairing the Chemistry Section of the American Association for the Advancement of Science from 1987 to 1989, and serving as president of ACS in 1996. That same year, he wrote a widely acclaimed book for the general public describing chemistry's importance, "Chemistry Today and Tomorrow: The Central, Useful, and Creative Science." Last year, C&EN's readers named him as one of the top 75 contributors to the chemical enterprise in the past 75 years.

Born in Rahway, N.J., in 1931, Breslow grew up in a community well endowed with research chemists, thanks to the presence there of Merck Research Laboratories. In particular, Max Tischler, the organic chemist who directed the laboratories in the 1950s and 1960s, was a family friend who gave young Ron an organic chemistry textbook when he was still in grade school.

In high school, Breslow did experiments in his basement that helped him win a trip to Washington, D.C., in 1948 as a Westinghouse Science Talent Search finalist. Thinking he wanted a career in medical research, he majored in chemistry at Harvard University, receiving a B.A. degree in 1952, and entered Harvard's graduate program in medical science. After a year in the program that earned him a master's degree, Breslow returned to the chemistry department to complete his Ph.D. degree in 1955 under the supervision of Harvard's master synthetic organic chemist, Robert Burns Woodward. Following a postdoctoral year in Cambridge, England, he joined the chemistry faculty at Columbia in 1956, where he has remained ever since.

His wife, Esther, completed her Ph.D. degree in biochemistry when they came to New York from England. She is now a professor of biochemistry at Cornell Medical College in New York City. They have two daughters, Stephanie and Karen, who are both attorneys.

Early in his research career, Breslow made seminal discoveries in two completely different areas of organic chemistry, and that breadth of research interest continues to characterize his work. In 1957, he and his students synthesized the cyclopropenyl cation, the simplest possible aromatic ring. Meanwhile, he and other students were working out aspects of the mechanism by which the coenzyme thiamine pyrophosphate helps facilitate aldehyde transfer reactions in biological systems.

Both projects were the beginnings of threads that continue in Breslow's research today. Novel conjugated organic molecules, of which the cyclopropenyl cation is the simplest, have blossomed into an entire field of nonbenzenoid aromatic chemistry. And his early work to understand enzyme-catalyzed reactions has grown into a career-long quest to learn nature's tricks for doing exquisitely selective chemistry and apply those methods in new ways.

"From the beginning, I was quite interested in the properties of things that had the 'wrong' number of electrons," Breslow says. The cyclopropenyl cation, for example, with only two electrons, was the first compound shown to have the increased stability of an aromatic system without having six electrons in its ring. Later, his group showed that the cyclopropenyl anion, which has four electrons, is actually less stable than its nonring counterpart, the allyl anion.

Most people at the time thought that adding two electrons to the ring of a cyclopropenyl cation would simply cancel out the stabilizing effect of the first two, Breslow recalls. "But we thought the anions would be far worse than normal molecules, that they would, in fact, be 'antiaromatic,' " he says. "We invented the word when we found the property." Simple quantum mechanical energy calculations don't predict this destabilizing effect, Breslow notes. "At the time we did it, there wasn't good theory to support it; it just seemed like a very good possibility." Later on, "better calculations made it clear that what we had found was, in fact, theoretically sensible."

Work on these small-ring aromatic and antiaromatic systems continues in Breslow's lab. Some of his current students, for example, are trying to make stable, isolable derivatives of the cyclopropenyl anion. "Theory predicts that these derivatives will have triplet ground states, but that's not established yet," Breslow explains. "There are some theoretical arguments that ground-state triplet molecules might be used as the basis for ferromagnetic materials, so this work now ties in to materials science in an interesting way."

Another continuing area of Breslow's research has been to study biological systems to work out how they do their chemistry and then to use that insight to expand the repertoire of organic chemists. That's a "biomimetic" approach, another word Breslow coined. The biomolecules Breslow seeks to mimic and understand are enzymes, with their ability to catalyze very selective chemistry.

The essence of the biomimetic approach is easy to understand. "It would be a lot easier to invent the telephone now that we know it can be done," Breslow says. "By the same token, it should be a lot easier to make enzymes now that we know that there are such things and that they really work."

Many chemists--including Breslow--have tried to apply the insights of physical organic chemistry to understanding the mechanisms of enzyme catalysis. "That's a very good field," Breslow says, "but I was much more interested in trying to make artificial enzymes. That's what really appealed to me." For one thing, the ability to duplicate is the real test of the scientist's understanding of how enzymes work. In addition, Breslow saw the effort to build artificial enzymes as a way to extend the range of organic chemistry. "Organic chemistry is still in many ways fairly simple, compared to the subtlety of enzyme-catalyzed reactions," he says. "Certainly that was true when we began, and it still is, to a large extent."

The biomimetic approach is one of chemistry's major frontiers today, and Breslow was one of the first to see its possibilities. "He certainly influenced me at a very early stage in my own career," says Caltech's Dervan. "Breslow realized that just as chemistry has profoundly driven biological discovery, the biological world could, in fact, drive new discoveries in chemistry. New and fundamentally important chemical principles would be uncovered by attempting to mimic biological functions such as catalysis, recognition, cooperativity, charge separation, and electron transfer. In his own 'bottoms up' approach to catalysis design, Breslow was asking: 'What are the fundamental principles by which a chemical reaction can be accelerated? If I can build an artificial catalyst, it may be that I understand it.' "

Unlike an organic chemist, an enzyme can attack a target molecule in a way that's controlled entirely by geometry, with little or no concern for intrinsic chemical reactivity. "An enzyme has no problem chewing off a saturated methyl group while leaving double bonds alone," Breslow notes. "We wanted to impose geometric control of that sort on chemical reactions."

Many of the molecules Breslow has synthesized to mimic the geometric control of enzymes are built on a cyclodextrin framework. These doughnut-shaped molecules are composed of glucose units--usually six to eight of them--joined together to form a ring. In aqueous solution, the hole of the doughnut forms a hydrophobic cavity that can bind hydrophobic regions of other molecules in much the same way that many enzymes bind their substrates. Additionally, the two rims of a cyclodextrin ring offer hydroxyl groups that can either react with substrates directly or be used to attach catalytic or functional groups.

In addition to their useful chemical properties, cyclodextrins are attractive because "you can buy them by the barrelful, and you don't have to synthesize them yourself," Breslow points out. Originally, he had intended to use them "to find out what was feasible," and then refine his systems by synthesizing new molecules with hydrophobic cavities that were fine-tuned to specific applications. His group has done some total syntheses of this type over the years, making artificial hydrophobic binding cavities from aromatic hydrocarbons, for example, instead of sugars. Such molecules can have advantages over cyclodextrins, including greater stability, particularly in acidic conditions. Often, though, total synthesis has turned out to be "a big pain in the neck, compared with just starting with something that's already available," Breslow notes.

"The first thing we showed using cyclodextrins was that we could actually catalyze a selective aromatic substitution reaction," he recalls. The reaction, the chlorination of anisole (also called methoxybenzene) in aqueous solution by hypochlorous acid, ordinarily occurs at both the ortho and para positions. But when cyclodextrin is added, anisole binds within the hole of the doughnut, effectively blocking chlorination at the ortho position. At the same time, the cyclodextrin catalyzes substitution at the para position through a mechanism that involves transfer of a chlorine atom to a cyclodextrin hydroxyl group that's nicely positioned to relay the chlorine to that spot on the anisole ring. "We were able to show that an aromatic compound would go into the cavity of the cyclodextrin, and the cyclodextrin would then deliver a reagent to the part of the compound it could reach, and not to other parts. Then the molecule would come out and another one would go in, so we got real turnover of the catalyst."

From there, the group began attaching catalytic groups to cyclodextrins to promote selective chemical reactions. By attaching two imidazoles, for example, they were able to imitate the acid-base catalysis of enzymes such as ribonuclease A. Other studies linked two cyclodextrins with a catalytic group between them. Such systems can grab both ends of a substrate and hold it in exact position for the catalyst to attack it, leading to rate accelerations that can be greater than a million-fold.

Two cyclodextrin projects are currently under way in Breslow's lab. In one, cyclodextrin dimers, but not monomers, bind selectively to the hydrophobic side chains of certain peptides. When the side chains are part of an enzyme, this binding can greatly diminish the enzyme's activity. "We're quite interested in the possibilities of these things as materials that can modulate enzyme activity," Breslow says, noting that many useful drugs work by modulating enzymes. Breslow's cyclodextrin dimers may be shutting down the enzyme because their binding changes the enzyme's shape so that it no longer binds as well to its substrate. However, many enzymes are themselves dimers, held together by interactions that almost always take place within their hydrophobic regions. So a hydrophobic binder, like the cyclodextrins, could work by interfering with the process of bringing the enzyme's subunits together. "We have evidence for both types" of inhibition, Breslow says.

In the second project, students are constructing systems with two and three cyclodextrin rings, linked together with appropriate spacer groups, that can begin to recognize specific peptide sequences. By positioning charged moieties on the links between the cyclodextrins, Breslow and his students hope to be able to build molecules that can interact with both the hydrophobic and hydrophilic regions of peptides in a way that can be selective.

Yet a third research strand has been under way in Breslow's lab since the mid-1970s. At that time, colleagues at Columbia's medical school asked Breslow to help them work to understand how certain solvents such as dimethyl sulfoxide and butyric acid were able to cause many types of cancer cells to change from rapidly dividing, undifferentiated, juvenile-appearing cells into seemingly normal, nonproliferating ones. Their goal was to develop drugs that would produce this same transformation at safe and practical dosages.

When cells develop from their juvenile form, called stem cells, they follow one of two paths, Breslow explains. On one path, they proliferate rapidly to produce more stem cells, which perform very few of the biochemical functions of mature cells. Cells on the other path mature into differentiated, adult cells that generally don't proliferate. Some cancer researchers propose that cancer occurs when the balance between the two pathways shifts, so that too many cells proliferate and not enough mature to their full adult form. Solvents like dimethyl sulfoxide seem to be able to reprogram immature, proliferating cells so that they become differentiated.

"Now you might wonder, what on Earth does that have to do with anything that we do here?" Breslow asks. "But it turns out to be intellectually related." Breslow thought large volumes of solvent might be needed to trigger cancer cell differentiation because the solvent molecules had to saturate two different binding sites within the cells. If so, and if the two binding sites are close together, Breslow reasoned, it might be possible to build a molecule that could bind both sites at once by linking two solvent molecules together with a connector of the appropriate length between them. Then when one end of the molecule binds, it would position the other end to bind as well.

"We simply linked two solventlike molecules with a carbon chain, and it turned out we were lucky, and the idea was right," Breslow says. He and his students have now made over 700 molecules of this general type, and their medical collaborators have tested many of them for anticancer activity. "The molecules that are effective have a hydrophobic amide at one end and a hydroxamic acid at the other, and the chain between them has to have about six carbons," Breslow says.

Some of the most potent of these compounds have been screened for anticancer activity in tests at the National Cancer Institute. The results of these preclinical tests seem quite positive, Breslow says. The best compounds inhibit the growth of many types of cancer cells without actually killing the cells. In fact, all of the toxicity studies on the compounds seem promising, so far, he notes. One of the compounds is slated to begin clinical trials this summer, to be conducted in conjunction with colleagues at Memorial Sloan-Kettering Cancer Research Institute and the National Cancer Institute.

There is a common thread that runs through all the projects in Breslow's laboratory. "We like to make new molecules that we think will have interesting properties," he explains. When you make a new molecule, he notes, you're bound to "find out something that you wouldn't know otherwise. And the fun of research is to learn new things." Learning to make new molecules is also invaluable to the education of chemistry students, he believes. "It's the great tool that organic chemists have that nobody else can do."

Everyone makes molecules in Breslow's lab. Frequently that means doctoral candidates have two-part theses in which they might do physical-organic studies in one part and organic synthesis in the other. "I've had physical chemists take degrees with me, but they still make some molecules," Breslow says.

Currently, 14 people are in Breslow's group, including graduate students, postdocs, and one undergraduate. Nearly all of them will synthesize one or two compounds designed in some way to be better anticancer compounds. "We almost run it as a lottery in the group," Breslow says. "Everybody gets good experience in making something, and, of course, students are always excited about the possibility that their compound will be the big hit!"

Breslow's broad interests extend well beyond chemistry. He's an accomplished pianist whose repertoire extends from popular songs to improvisational jazz. He plays everywhere, friends say. He can often be spotted playing the piano in a hotel lobby at an ACS meeting, for instance, and he recently bought and donated a piano to Columbia for the chemistry lounge. He's also an occasional scuba diver and skier.

At 68, Breslow is at an age when people's thoughts often turn toward retirement. Not his. The only time he thinks about retirement, he says, is when he tries to persuade colleagues not to do it. But then, agelessness has long been an important part of Breslow's persona. As UC Berkeley's Bergman puts it: "He just doesn't seem to age, certainly not intellectually. Talking to him now is like talking to him 30 years ago. He's got the same enthusiasm, the same excitement about chemistry."

Breslow himself says, "There are people who believe that academics put too much of their lives into their work. What they don't realize is that we do it because it's so much fun!"

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Copyright © 1999 American Chemical Society