SCIENCE
Barton Is Second Chemist To Receive NSFs Waterman Award Jacqueline K. Barton, assistant professor of inorganic and biophysical chemistry at Columbia University, will receive this year's Alan T. Waterman Award from the National Science Foundation. The award, which includes a medal and NSF grants of up to $100,000 a year for three years of research and advanced studies, is given each year to an outstanding young researcher in any field of science, mathematics, or engineering. Barton, who is 32, is the second chemist to win the award since it began in 1975 and the first woman to receive the award. Erich Bloch, NSF director, says Barton has "developed the experimental tools necessary to bridge the fields of molecular biology and inorganic chemistry which have the potential for profoundly affecting the future course of scientific research in this area." In an interview with C&EN's Rebecca L. Rawls, Barton describes these tools and the applications she sees for them in probing problems in molecular biology. What is the focus of the work in your laboratory? What we are trying to do, essentially, is to exploit inorganic chemistry to study biological molecules. We want to use inorganic coordination chemistry to design molecules that recognize specific DNA sites. We are very interested in DNA structure and conformation and the relationship between DNA structure and its biological expression from a chemical point of view. The molecules that we have been looking at allow us to look very sensitively at local DNA conformation, at a little bit of one conformation in the presence of predominantly another conformation. The idea is to get site-specific reagents that can tell us something about the DNA structure. What we have done, in particular, is to design molecules using chiral trisphenanthroline metal complexes. These chiral complexes discriminate in binding to DNA based upon the DNA helicity and the chirality of the metal complex. So right-handed complexes bind preferentially to right-handed DNA, called B-DNA. Left-handed complexes don't bind well to right-handed DNA, but they bind very well to left-handed, or Z-, DNA. That, then, gives us a very sensitive probe for Z-DNA. We are also trying to extend the idea to look at other conformations and to add sequence specificity to our reagents. But the main idea at the moment is to be able to discriminate between Z- and B-DNA. Which metals do you use in your complexes? It depends. We pick the metal for what we want to do. We've used ruthenium trisphenanthroline complexes
when we wanted a spectroscopic probe of DNA structure. We use cobalt(HI) complexes when we want to do site-specific chemistry. It is known that if you irradiate Co(III) complexes with ultraviolet light, you can get them to photoreduce, and if you do that in the region of the DNA helix, you can then oxidatively cleave the DNA. In other words, we are delivering redox chemistry to the Z-DNA site. That tells us not only how much Z-DNA we might have, but where it is along the DNA strand. And it also in some sense might mimic the way enzymes recognize specific sites. It's obviously not the same kind of chemistry, but the notion of being able to recognize a site based upon conformation and do chemistry on it certainly may resemble what enzymes do. April 22, 1985 C&EN
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Science
We are very interested in the relationship between DNA structure and its biological expression from a chemical point of view
Are there enzymes that are conformation-specific? There are DNA-binding enzymes that bind to discrete sites for which there is no sequence homology. They are probably recognizing a specific conformation, but we don't know for sure. I wonder whether conformation-specific recognition is something that nature takes advantage of. We are actually using very simple coordination complexes, and yet we can achieve highly specific recognition. Now a particular DNA sequence—an alternating purine and pyrimidine sequence—has a tendency to adopt the Z conformation. We are just taking a reagent and binding to it. Sequences can adopt a different conformation, a different shape, and we can design a reagent that recognizes that different shape. In some sense, our technique is indirect sequence-specific recognition because the particular sequence imparts a different conformation. Do these Z-DNA regions have any biological importance? That's what we are hoping to find out. Z-DNA was discovered by Alexander Rich [professor of biology, Massachusetts Institute of Technology] when the first three-dimensional crystal structure of a DNA fragment was determined. Our reagent is probably one of the most sensitive chemical probes for Z-DNA, but there are also nonchemical probes. There have been antibodies that recently have been elicited against Z-DNA, and people are now beginning to see under what conditions one gets Z formation. With our cobalt reagent, we have been able to map where Z-DNA sites occur. We have used it on plasmids into which have been inserted short Z segments, and it cuts specifically there. Most recently, we have looked at DNA segments as they occur naturally in a plasmid (pBR322) and in a virus (SV-40). We are beginning to 26
April 22, 1985 C&EN
see a correlation between the location of Z-DNA sites and genetic expression. In fact, what we are seeing is that Z-sites seem to be associated with the ends of genes. At the very least, it's an indication that DNA's chemical conformation can have some biological involvement, some role in genetic expression. Now we want to look at that a lot further and see whether or not it proves to be a general phenomenon. A number of laboratories are probing the possibility of using coordination complexes that bind to DNA as chemotherapeutic agents. Are you doing any work of that sort? Our main interest is in designing site-specific reagents that bind to DNA. Whether they will be useful pharmacologically remains to be established. However, we have now designed complexes that bind covalently to the DNA: bisphenanthroline ruthenium complexes. These complexes share with their platinum(II) analogs the preference for binding to guanine sites, and we think they might be interesting starting points for designing chemotherapeutic agents. It was surprising to me when we first looked at these chiral complexes that stereochemistry hadn't been exploited earlier in designing reagents that bind to specific DNA sites. To design a specific reagent— for a pharmacological application, or for any other—it seems that you ought to take advantage of DNA's being an asymmetric molecule. And so we are doing that. It sounds as though this field is just beginning to break open. Yes, it is! Inorganic complexes are really nice. They have varied geometries, they are rigid, you can define
We are using very simple coordination complexes, yet we can achieve specific recognition
exactly what it is you are talking about, and you can use the metal to do whatever chemistry or whatever spectroscopy you want to do. That's something I learned as a graduate student [in Stephen J. Lippard's laboratory, then at Columbia University. Lippard is now a professor of chemistry at Massachusetts Institute of Technology]. czs-Dichlorodiammineplatinum(II), I understand, is now one of the leading antitumor drugs. Trisphenanthroline ruthenium is a complex that people use widely for electron-transfer reactions. They are very simple coordination compounds. If we can get h i g h l y specific reactions w i t h such simple complexes, and anticancer drugs can be found with such simple complexes as cisplatin, just think what we may be able to do once we start fine tuning this. •
