science/technology

NATURAL PRODUCTS' SCOPE EXPANDING IUPAC symposium showcases breadth of approaches chemists use to understand complex molecules from natural sources

A. Maureen Rouhi C&EN Washington

U nder ordinary circumstances, Anita J. Marsaioli and Richard J. Roberts would not have expected to be con­

tributors to the same scientific meeting. Marsaioli, a chemistry professor at the

University of Campinas, Sao Paulo, Brazil, has been studying the pollinating behavior of solitary bees. Roberts, winner of the 1993 Nobel Prize in Medicine and a direc­tor of research at New England BioLabs, Beverly, Mass., is probing the phenome­non of base flipping in oligonucleotides.

Remarkably, last month in Chicago, Marsaioli and Roberts presented their re­search at the same forum, the 20th Inter­national Union of Pure & Applied Chem­istry (IUPAC) Symposium on the Chemis­try of Natural Products. The meeting was attended by about 600 other researchers from diverse disciplines, confirming that natural products research is reaching be­yond its traditional confines.

As Sir Derek H. R. Barton—winner of the 1969 Nobel Prize in Chemistry; pro­fessor of chemistry at Texas A&M Univer­sity, College Station; and president of the symposium—noted in his welcoming re­marks, the meeting reflected the impor­tance of physical methods for structure determination and the great strides made in synthesis. But the profound discover­ies in the future could be at the interface of disciplines, he said, noting the new possibilities offered by the powerful methods of molecular biology.

The Chicago meeting featured many firsts. It was the first time that IUPAC's natural products symposium was held in the U.S.

For the first time, industry played a key role in planning and financing. Sever­al industrial chemists organized the meet­ing, and 25% of the speakers came from industry. Companies such as Abbott Lab­oratories and G. D. Searle provided sig­nificant financial support.

34 OCTOBER 21, 1996 C&EN

Participants got a rare opportunity to listen to lectures by six Nobel Laureates as well as some of the other brightest names in chemistry. To maximize interaction among participants, the organizers used a single venue and scheduled only one ses­sion at a time.

The diversity of personalities mir­rored the breadth of the coverage, which ranged from well-established pursuits to cutting-edge work that some may find hard to regard as natural products re­search. Many speakers said they wel­comed the broad net cast by the organiz­ers because thev found it exciting to speak to a mixed audience tor a change and not to the same people they always see in the usual meetings they attend.

Marsaioli's work fits in the classical tradition of natural products re­search. Recently, in col­laboration with botanist Volker Bittrich at the University of Campinas and others, she unrav­eled the mystery of why some bees seek resins as their reward for polli­nating the colorful flow­ers of the genus Clusia.

Some bees of the ge­nus Euglossa use the res­ins—mostly polyisopreny-lated benzophenones— to build their nests, Marsaioli has found. The resins slowly polymerize during nest construction, providing waterproof pro­tection to the bees. And because some of the resin components show bio­logical activity, Marsaioli suspects the resins also protect bee larvae from viruses and bacteria.

Solitary bee collects resins as it gathers pollen from a male flower of Clusia grandiflora.

Similarly, the work described by Prin­cess Chulabhorn Mahidol is natural prod­ucts research in the classical tradition. The princess is the youngest child of Thailand's King Bhumibol and Queen Sirikit. She received a Ph.D. degree in or­ganic chemistry from Mahidol University in Bangkok and is working on an M.D.-Ph.D. degree from the University of To­kyo Medical School.

A highly visible patron of science for the developing world, Princess Chula­bhorn currently is a professor of organic chemistry at Mahidol University and heads the Bangkok-based Chulabhorn Re­search Institute. One of the major thrusts of this multidisciplinary research center is the use of natural products from Thai medicinal plants to treat diseases, espe­cially cancer.

In addition to describing her research work, the 39-year-old princess appealed for preservation of natural resources. "It is ironic," she said, "that while patent laws protect corporations and individuals from having their ideas stolen, nature's biodiver­sity and ethnomedical knowledge are largely unprotected." She also called on the pharmaceutical industry to compen-

sate source countries tor discoveries ot bi­ological agents that lead to profits.

A staple of natural products research is structure elucidation. This work has become routine with X-ray diffraction and spectroscopic methods. But advanc­es in determining structural details and properties continue to be pursued, as ex­emplified by the work described by chemical physicist and crystallographer ferome Karle.

Karle received the 1985 Nobel Prize in Chemistry for helping to develop the mathematics used in direct methods of crystal structure determination. At pres­ent, he is refining a technique called quan­tum crystallography at the Naval Research Laboratory, Washington, D.C., where he is chief scientist and chairman of the Labora­tory for the Structure of Matter.

Quantum crystallography is a combina­tion of quantum mechanics and crystallog­raphy. X-rays are diffracted by electron dis­tributions around atoms. Therefore, the re­sults of a diffraction experiment can lead to a description of these same electron densities, Karle pointed out in Chicago. At the same time, electron densities can be represented by quantum mechanical mod­els with the use of wave functions.

Starting with coordinates from X-ray diffraction experiments, the technique involves a least-squares process in which the quantum mechanical model is re­fined to optimize agreement with the crystallographic data, Karle explained. With good crystallographic data, quan­tum crystallography has the potential to yield "rather accurate wave functions, which could lead to accurate evaluations of such features as molecular energy, electron density, electrostatic potentials, and charge distributions," he said.

A benefit from the mathematics of the technique is that wave functions of very large structures such as macromolecules can be calculated—by quantum mechan­ical methods alone—from carefully cho­sen fragments. This permits ab initio cal­culations for complex structures "with a computing time that increases essentially linearly only with the complexity of the molecule," Karle emphasized.

With coworkers Lulu Huang of Geo-Centers Inc., Fort Washington, Md., and Lou Massa of City University of New York, Hunter College, Karle has demon­strated the use of fragments to obtain wave functions for leu^zervamicin, a membrane-active peptide that facilitates potassium ion transport across bound­aries [Int. J. Quantum Chem., 60 (7), 479(1996)].

OCTOBER 21, 1996 C&EN 35

Base that has flipped out of the DNA helix lies snugly in the pocket of a DNA methyltransferase. ready for a reaction.

At the Chicago symposium, synthetic chemists, challenged and inspired by compounds with structures only nature can conceive, conveyed the diverse mo­tives for total synthesis. With many com­pounds, synthesis is driven by the need to produce large amounts so the com­pounds can be studied further or used to treat diseases. Such is the case with pacli-taxel, the potent anticancer compound that Bristol-Myers Squibb is marketing under the trademark Taxol.

Although several total syntheses of pa-clitaxel have been reported, the molecule still grips synthetic chemists. "Much re­mains to be done," said Paul A. Wender, noting that the molecule presents a wealth of "opportunities for fundamental and ap­plied advances." Working with an interna­tional team, the Stanford University chem­istry professor recently completed the syn­thesis of paclitaxel based on pinene.

Pinene is a superb starting material, said Wender in Chicago. It provides 10 of the 20 carbon atoms in the molecule's tri­cyclic core, and its chirality matches that of the required structure. Pinene also is readily available and cheap.

More important, perhaps, than the prize of achieving a total synthesis is what comes after, the design of simpler analogs. "Nature did not invent [paclitaxel] to cure cancer," said Wender. "You can remove the frills, and it still will work." His group is designing nontaxane compounds that would function like paclitaxel.

For other synthetic chemists, synthesis is almost a purely intellectual exercise. For example, Columbia University professor

emeritus oi cnemistry <jriiDert stora re­galed the Chicago audience with what he called "long-standing stereochemical prob­lems" in the classical syntheses of various compounds, including tetracycline.

It's not as if Stork wants to produce the antibiotic by synthesis. Rather, he said, it's taking on the construction prob­lems these targets present to advance the whole field of synthesis, especially in the area of stereochemistry.

Stork described his group's latest ac­complishment, the first total synthesis of the steroid (+)-digitoxigenin. Its trisac-charide derivative—called digitoxin—is a component of foxglove (Digitalis) ex­tracts. These extracts are powerful car­diotonic agents and have been used to treat atrial fibrillation.

The total synthesis is "the first that does not start from an optically active natural product," said Stork. Prior to this work, only partial syntheses from readily available steroids have been achieved. A crucial construction was accomplished through vinyl radical cyclization.

A. Ian Scott, a chemistry professor at Texas A&M University, takes a different approach to assembling complex natural products such as vitamin B-12. This mole­cule is perhaps one of the most complicat­ed ever prepared chemically by human ef­fort. Its first preparation used the energies of more than 100 postdoctoral fellows working with Robert B. Woodward at Har­vard University and Albert Eschenmoser at the Swiss Federal Institute of Technology in Zurich over a 10-year period.

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CIRCLE 16 ON READER SERVICE CARD

38 OCTOBER 21, 1996 C&EN

science/technology completely solved, Scott said. But vitamin B-12 has been full of surprises, and "now comes the greatest surprise," he told the symposium. "There are two parallel, non-identical routes to vitamin B-12."

Clearly, an anaerobic route must exist because primitive anaerobes have been making the vitamin for about 4 billion years now. (Methanogenic bacteria that make vitamin B-12 can be dated to about 4 billion years ago.) What's fascinating is how different the routes are. With aer­obes, the fundamental ring system, called the corrin structure, is assembled through reactions requiring oxygen as a cofactor. Cobalt doesn't get in until after the corrin has been formed. Anaerobes, on the other hand, use cobalt as an early cofactor so that when the corrin ring is assembled, it already contains cobalt.

The findings imply different mecha­nisms for one of the intriguing steps in the biosynthesis—contraction of the macrocy-clic ring. Unlike the 20-membered rings in heme or chlorophyll a, which are structur­al cousins of vitamin B-12, the ring in the vitamin has only 19 carbons.

According to earlier work, the macro-cycle contracts in the aerobic pathway through an 02-dependent hydroxylation. Scott's recent work has revealed a new intermediate in the anaerobic pathway that suggests the ring contracts with the help of cobalt.

Will there be more surprises? "It seems likely that only two pathways exist," Scott said. His team has compared the genes of

several anaero­bic organisms with those of the newly dis­covered form of ancient anaero­bic life, the ar-chaeon Meth-anococcus jan-naschii (C&EN, Aug. 26, page 31). They find that anaerobic organisms and the archaeon have a closely related set of genes for mak­ing vitamin B-12. On the other hand, aer­obes, which date from about 2 billion years, have some vita­min B-12 genes Roberts: base flipping is a widespread mechanism

Marsaioii: poliinating behavior of bees

Continued from page 35 Scott now prepares the vitamin by mix­

ing the amino acid building block with en­zymes and cofactors in a flask and leaving the mixture overnight. He finds that, like what happens in the cell, each enzyme does its job—the precursor is transformed, as if on an assembly line, to the product.

That's the easy part. The multienzyme one-flask synthesis could be done only after Scott's team—in parallel with the teams of Alan R. Battersby at Cambridge University, England, and of Francis Blanche at Rhône-Poulenc Rorer, Paris-determined nature's pathway to vitamin B-12. First, they had to find the cluster of genes responsible for vitamin B-12 synthe­sis. Then they had to separate each gene, sequence it, and clone it. Finally, to get sufficient amounts of the enzymes, they had to overexpress the gene products through genetically engineered bacteria.

The painstaking, convoluted, yet ex­hilarating odyssey took 25 years. The ef­fort required much detective work, with scientists using genetics, molecular biolo­gy, enzymology, organic chemistry, and nuclear magnetic resonance spectrosco­py to decipher the process leading to the vitamin's natural synthesis. In 1994, Scott's team reported that it had replicat­ed in a flask containing 12 enzymes the 17 steps nature takes to convert the pre­cursor, 5-aminolevulinic acid, to a cobalt-free intermediate, which is easily con­verted to the active vitamin [Chem. Biol, 1,119(1994)].

But there's more. Having achieved the genetically engineered synthesis, "it might have been assumed that the problem of how nature makes the vitamin had been

with no counterpart in anaerobes, mat nature has conserved both pathways to this extremely complex molecule is per­haps the greatest surprise of all," he said.

Although genetically engineered syn­thesis can't be a competitive process for producing bulk quantities of vitamin B-12, Scott believes the approach will be eco­nomically viable for other natural prod­ucts, including anticancer compounds such as vincristine and paclitaxel.

One of the striking features of the Chicago symposium was the intense in­terest in oligonucleotides. The field's vi-brance came through so clearly that any­one with even just a vague notion of what's going on in this area would have been infected by the enthusiasm of the researchers who described their work. And it wasn't just because nucleic acid research was discussed clearly and with gusto by Roberts and two other Nobel Laureates—Thomas R. Cech and Michael E. Smith, the 1989 and 1993 winners in chemistry, respectively. The interest in nucleic acids ranged from how DNA he­lices are unzipped to exploring the or­ganic chemistry of nucleic acids, under­standing their behavior, discovering new properties, and designing small mole­cules that recognize specific sequences.

Roberts' long-standing interest in re­striction enzymes, the workhorses of the biotech industry, helped in the discovery of split genes. For that discovery, he was honored with the first major award of his career: the 1993 Nobel Prize in Medicine.

Calling an old friend by a different name How should one refer to that antican­cer compound originally isolated from the Pacific yew tree without elic­iting cease-and-desist warnings from lawyers? Not by its original name, ac­cording to Bristol-Myers Squibb. Be­cause since 1992, the pharmaceutical company has owned as a registered trademark the familiar name that un­til recently was used universally to identify the compound.

The trademark cops must have missed the 20th IUPAC Symposium on the Chemistry of Natural Products held last month in Chicago. Two au­thors used the registered name in their titles and throughout their talks. Many others used the original name as they chatted outside the symposium hall. Not a few were sur­prised to learn the original name no longer should be used casually.

The original name "should only be used to refer to the anticancer prepara­tion sold by Bristol-Myers Squibb Co.," Stephen Chesnoff notified C&EN in early September. Chesnoff is the com­pany's associate general counsel for trademark and copyrights. The notice was prompted by a C&EN article that referred—inappropriately, according to Chesnoff—"to a substance derived from the Pacific yew tree as 'taxoL' "

Chemists, and C&EN, are coming around to using paclitaxel, the ap­proved generic name—even though according to Monroe E. Wall, "Pacli­taxel is an ugly-sounding name." Wall is a chief scientist at Research Triangle Institute in Research Triangle Park, N.C. He named the anticancer com­pound from the Pacific yew tree when all that was known about its structure was that it had a hydroxyl group.

Because the Pacific yew tree belongs to the genus Taxus, it seemed reason­able that the compound has a name that uses part of the genus name— "tax"—and gets the rest of its name from being an alcohol—"ol," Walls tells C&EN. He's "basically surprised but not resentful and, to some extent, amused" that the name he created "could indeed be trademarked"

It won't be easy calling an old friend by a different name. The original name was first used in June 1967, in a research progress report prepared for the National Cancer Institute. It first appeared in the peer-reviewed litera­ture in 1971 [/. Am Chenu Soc, 93, 2325 (1971)]. In 1993, the new generic name paclitaxel was published as the U.S. adopted name.

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OCTOBER 21, 1996 C&EN 39

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science/ technology

Restriction enzymes always are accom­panied by a DNA methyltransferase that adds a methyl group to a specific se­quence. The restriction enzyme recogniz­es and cuts the same sequence if it is not methylated. Roberts' research has revealed that some DNA methyltransferases flip their target base 180° out of the helix, po­sitioning the base in a pocket in the en­zyme where the chemistry takes place. Others have found that this phenomenon, called base flipping, allows DNA repair en­zymes to remove errant bases.

Roberts has proposed that base flip­ping is a more widespread mechanism and that it could be the common first step in unzipping a DNA helix, which both DNA and RNA polymerases need to do before they can function. How this first step occurs is not known, and base flipping could be the key.

Steven A. Benner, chemistry profes­sor at the Swiss Federal Institute of Tech­nology, pointed out that before 1985 oligonucleotides had been overlooked by synthetic organic chemists, such that

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CIRCLE 3 ON READER SERVICE CARE

40 OCTOBER 21, 1996 C&EN

Karle: determine structural details

Princess Chulabhorn: preserve resources

"the theory of nucleic acid chemistry is underdeveloped in the organic chemical sense."

The situation has "created enormous problems for those trying to use nucleic acids and their derivatives as pharmaceu­tical agents," noted Benner. The field of antisense therapeutics, for example, would benefit immensely from trying to examine oligonucleotides "in a very nat­ural product sense," he said. That is, by systematically altering the structure and observing the change in reactivity and properties.

Research in antisense therapy has fo­cused on modifying the backbone as a way to improve therapeutic properties. The strategy is based on the accepted no­tion that for molecular recognition the

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Chlorinated porphyrin acts like mammalian liver

Halogenated metalloporphyrins can oxi­dize various drugs to the same metabo­lites produced by mammalian livers, ac­cording to research at the University of British Columbia, Vancouver. These mol­ecules could complement, perhaps even replace, the use of animals in studies of drug metabolism that are required by the pharmaceutical industry.

Chemistry professor David H. Dolphin reported these findings at the 20th IUPAC Symposium on the Chemistry of Natural

Products, held last month in Chicago. Dolphin's research has shown that high­ly chlorinated porphyrins, such as the one shown below left, oxidize the analge­sic lidocaine. The reaction gives not only all the known mammalian metabolites of lidocaine but also three other com­pounds, which could be metabolites, too. Similar results are obtained with another drug, aminopyrine. Thus, the porphyrins are doing what mammalian livers do.

The chlorinated porphyrins are like cytochrome P450s, said Dolphin, who is also vice president for tech­nology development at QLT Photo-Therapeutics Inc., Vancouver. Cyto­chrome P450s are heme proteins that are powerful oxidants in living systems. Studying how they work is a complex undertaking, because the iron porphyrin where the chemistry takes place lies deep within the pro­tein. Dolphin's research has focused on designing molecules that mimic cytochrome P450s without being en­cumbered by the protein. The "syn-

Dolphin: unencumbered cytochrome P450s

thetic livers" are robust and catalytically very active, said Dolphin. Being more pow­erful oxidants than dichromate or per­manganate, they are good candidates as catalysts for organic synthesis.

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OCTOBER 21, 1996 C&EN 41

science/technology

Nature has conserved two pathways to vitamin B-12

Ancient genes in anaerobes (4x 109 years)

HoN.

Modern genes in aerobes (2x 109 years)

cbiL

cbiH

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5-Aminolevulinic acid

S-Adenosylmethionine

Nicotinamide adenine dinucleotide phosphate

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Cobyrinic acid

H N ^ ° \ CONH2

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Hydrogenobyrinic acid

Vitamin B-12

Vitamin B-12 biosynthesis starts with colorless 5-aminolevulinic acid. Insertion of oxygen or cobalt, along with ring contrac­tion and methylations, leads to colored chromophores. The question marks in the ancient genes indicate that the cbi counter­part to the known cob gene sequence is not yet known, or perhaps does not exist.

bases are the stars, with the sugars and phosphate linkers playing supporting roles as scaffolds.

Benner's work is showing that the backbone may be more than just a bit player. Working with nonionic RNA ana­logs, Benner and postdoctoral fellows Cle­mens Richert and Andrew L. Roughton have found that the repeating anionic charges in the phosphodiester backbone also control the molecular recognition properties of DNA and RNA [/. Am. Chem. Soc, 118,4518(1996)].

"The polyanionic backbone is not in­cidental," said Benner. Because the phos­phate groups of one strand repel those of a second strand, they force strand-strand interactions as far as possible from the backbone. Without this repulsion, other interactions—involving other parts of the strand, such as the sugars and the backbone itself—could become more

important than those between the Wat­son-Crick base pairs, making impossible the simple rules of molecular recogni­tion that nature has designed for nucle­ic acids.

Benner's study of nonionic RNA ana­logs also revealed that oligonucleotides have a tendency to fold, just like pro­teins. But because of the negative charge on the phosphate linkages, natural nucle­ic acid strands are more likely to extend than fold. "They are stretched out," Ben­ner explained, "preorganized for binding to the complement."

The repeating anionic groups on the backbone also make oligonucleotide properties independent of the base se­quence. "This characteristic is very use-mi for an encoding molecule," said Ben­nett. That's why DNA keeps functioning despite mutations, whereas even one amino acid substitution in a protein can

cause huge changes in the protein's physical and chemical properties.

For use in antisense therapy, nucleic acids with nonionic linkers might be bet­ter able to penetrate biological mem­branes. Benner's work suggests that de­signed nonionic oligonucleotide analogs should have features built into them that reproduce the unique effects of the phosphodiester backbone.

At Columbia University, chemistry professor Ronald Breslow also is doing work that has implications in antisense drug design while helping to explain why nature designed DNA as it is. With graduate student Terry L. Sheppard, Breslow recently examined the behavior of a DNA isomer based on 3-deoxyribose, instead of the normal 2-deoxyribose. The phosphodiester linkages in the DNA iso­mer are 2', 5', instead of 3', 5' in normal DNA. "You can make a very good case

42 OCTOBER 21, 1996 C&EN

Scott: parallel routes to vitamin B-12

that in primitive earth DNA based on 2',5' linkages could have been formed just as easily,'' said Breslow. "But nature doesn't use them. How come?"

It's because 2',5/-linked DNA can't bind to other DNA strands, whether linked at 2',5' or at 3', 5', his research suggests \J. Am. Cbem. Soc, 118, 9810 (1996)]. The different linkage causes a slight change in geometry that makes the DNA isomer un­able to "do the fundamental thing of mak­ing a double helix and passing genetic in­formation," explained Breslow. But al­though 2/,5/-linked DNA can't bind normal DNA, it is compatible with normal RNA, forming very strong helices. "It recognizes RNA but ignores DNA, and it is not de­stroyed by human nucleases," Breslow said. These properties make the DNA iso­mer a good candidate for development into an antisense drug. The isomer also could be used to detect RNA without in­terference from DNA.

Even as chemists treat DNA just like any other organic molecule, its natural role as the keeper of genetic information is inescapable. Research about events that can damage the genetic code, lead­ing to carcinogenesis, was described in Chicago.

The group of chemistry professor Jac­queline K. Barton at California Institute of Technology is finding that the DNA double helix is a good medium for elec­tron-transfer reactions over long distanc­es. Recently, they showed that charge migrating through the n stack of a DNA helix can cause oxidative damage at re­mote sites (C&EN, Aug. 26, page 9).

"The bad news is that we really may have to worry about DNA damage

Benner: anionic backbone is not incidental

caused by radicals that have migrated along DNA," she said in Chicago. "The good news may be that structural pertur­bations to the 71 stack of base pairs may protect sequences from damage by inter­rupting the path."

Oxidative chemistry mediated by DNA base pairs may also be the basis of an assay for the integrity of the DNA stack. Barton said such an assay could be useful in probing how proteins change DNA structure and in searching for en­zymes that cause base flipping, described by Roberts. She and coworkers also are finding that long-range charge migration can promote repair of a common photo­chemical lesion in DNA, the thymine dimer—where a cyclobutyl ring forms between two thymine bases.

Studies by chemistry professor Cynthia J. Burrows and coworkers at the Universi­ty of Utah, Salt Lake City, and Steven E. Rokita, associate professor of chemistry at the University of Maryland, College Park, are helping to explain the carcinogenicity of nickel. They find that nickel-peptide complexes—the form in which nickel would exist in cells—can damage DNA. When exposed to ambient oxygen, these complexes generate products that cross­link with or cleave DNA. The common ox­idant monoperoxysulfate (HS05~) is key to the process.

Monoperoxysulfate, Burrows noted in Chicago, can be formed naturally in the atmosphere through autoxidation of sul­fur oxides. It is also formed by nickel-cat­alyzed oxidation of bisulfite (HS03"). Thus, nickel-peptides can catalyze this oxidation. The studies suggest that nick­el-peptides first catalyze the formation of

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»gy • J HH.H^-HJSS monoperoxysulfate from bisulfite. Then they catalyze the decomposition of monoperoxysulfate to a sulfate radical. This radical chelated to nickel is what at­tacks DNA, the team believes.

The ability to recognize specific se­quences in DNA has tremendous poten­tial application in biology and medicine. Caltech chemistry professor Peter B. Der-van reported in Chicago that he and co­workers have developed what looks like a general nonbiological approach to DNA recognition based on pyrrole-imida-zole polyamides.

Using a simple molecular shape and a two-letter aromatic amino acid code, these polyamides bind to DNA sequenc­es with affinities and specificities compa­rable with those of DNA-binding proteins [Nature, 382, 559 (1996)]. But unlike DNA recognition by proteins, the meth­od is general for any predetermined DNA sequence up to 11 base pairs in size, said Dervan. In at least one case, the poly­amides have been shown to permeate cells and inhibit the transcription of spe­cific genes. Dervan said they could be the basis for designing molecules that can be used to control gene-specific reg­ulation in vivo.

The Chicago symposium showed that natural products research will continue to be enriched by the crossing-over of disciplines and by the overflow to com­pounds that have been traditionally con­sidered outside the realm of natural prod­ucts. But maybe even more exciting is the use of natural principles to invent structures that behave like natural prod­ucts, as exemplified by research on self-assembling systems described by J. Fraser Stoddart, a chemistry professor at the University of Birmingham, England, and Jean-Marie Lehn, winner of the 1987 No­bel Prize in Chemistry.

"Chemists have developed unnatural methods to synthesize natural products," said Stoddart. "Yet unnatural products required in the construction of function­ing nanosystems will be constructed us­ing principles such as self-organization, self-assembly, and self-replication, which are natural in origin."

Understanding nature, imitating it, and using its principles to invent systems nature hasn't yet conceived all came to­gether in Chicago. "Fortunately, the new and the old and the future have always blended together in a harmonious whole for the subject of natural products chem­istry," according to Sir Derek Barton. "We have only to allow the evolution of our subject to continue."^

44 OCTOBER 21, 1996 C&EN

Short X-ray bursts push pulse envelope Scientists at Lawrence Berkeley National Laboratory (LBNL) in Berkeley, Calif., have created X-ray bursts that last only a few hundred femtoseconds, an order of magni­tude shorter than most currently available technology—a development that may soon add another dimension to the blossoming field of femtosecond spectroscopy.

The energetic punch of X-rays has probing power that surpasses optical ra­diation currently used in femtosecond techniques. Consequently, femtosecond X-ray pulses can monitor the motion of atoms in condensed matter as they react, vibrate, or change phases.

Optical radiation from femtosecond-pulsed lasers generally extracts informa­tion from the outer-shell electrons of at­oms. The behavior chemists observe in atoms with this technique is more akin to the motion of the loosely bound, ooz-

Schoenlein (back) and Leemans shown experimental apparatus at test facility.

ing white of an egg, rather than a com­pact inner yolk.

X-rays, however, are powerful enough to penetrate an atom's core electrons. The motion of these inner electrons provides a more accurate picture of the motion of at­oms themselves, which have vibrational periods on the order of 100 femtoseconds.

Several groups around the country, in­cluding one led by Kent R. Wilson, chemistry professor at the University of California, San Diego, have been pursu­ing various methods of generating ultra-fast X-ray pulses. Over the past few years, they have whittled down X-ray pulse times to the picosecond level.

The LBNL group, led by electrical en­gineer Robert W. Schoenlein and engi­neer Wim P. Leemans, managed to break

the picosecond barrier through a process known as Thomson scattering [Science, 274, 236 (1996)]. An electron beam accel­erated to nearly the speed of light inter­sects a pulsed-infrared laser at right angles. The laser pulse briefly deflects the elec­tron beam, causing the electrons to oscil­late and generating a quick spray of X-rays—albeit at fairly weak flux levels.

The process is similar to that which generates synchrotron radiation: As ac­celerated electrons are bent around a path, they give off X-rays.

The length of the X-ray pulses created by Schoenlein, Leemans, and colleagues are determined both by the length of the laser pulse and by the width of the elec­tron beam. So far, the group has produced pulses that last 300 femtoseconds, but they say additional focusing of the electron beam could bring the pulse time down to 50 femtoseconds.

"It's very exciting what they've done," Wilson says. "It's a difficult experiment, and they made it work.''

Ahmed Zewail, chemis­try professor at California In­stitute of Technology, says, "This study of Schoenlein [and his group] represents an important step for the generation of subpicosec-ond pulses. We now need to focus on increasing the photon flux to be able to use such pulse technology in real experiments."

Several approaches might solve the problem, Schoen­lein says: bigger lasers, big­ger electron accelerators, or higher repetition rates.

The Thomson-scattering approach was originally pro­

posed decades ago. But only in recent years have chemists realized the implica­tions such tools hold for them.

"Originally, the people interested in Thomson scattering were not in the same community as those interested in ultrafast spectroscopy," Schoenlein says. "It's really kind of the merging of two scientific interests."

The Berkeley group is studying an ul­trafast liquid-solid phase transition, which optical experiments suggest oc­curs in laser-excited silicon semiconduc­tors. This transition appears to happen on the 100-femtosecond scale. "But are the atoms really moving, or have you just perturbed the electronic properties?" Schoenlein asks.

Elizabeth Wilson

with