RON DAGANI, C&EN WASHINGTON

Once upon a time, organometallic chemistry and biology were viewed as disparate, mutually incompatible fields of research. Most organometallic compounds were thought to be inherently sensitive to water and oxygen--substances that are essential for biology. But as researchers delved deeper into organometallic chemistry, they began to realize that much of this field is quite compatible with biology. In fact, in the past decade or so, the two disciplines have merged to give birth to a new field--bioorganometallic chemistry.

Research in this nascent field focuses on compounds of biological interest where the chemistry of the metal-carbon bonds is a central feature, says Gérard Jaouen, a chemistry professor at Ecole Nationale Supérieure de Chimie de Paris (ENSCP). Jaouen, one of the field's most visible boosters, believes that organometallic compounds may offer innovative solutions to some difficult biological problems, such as breast cancer--his main research interest.

	Jaouen	Fish
	PHOTOS BY RON DAGANI

Chemist Richard H. Fish of Lawrence Berkeley National Laboratory in California, who also works in the bioorganometallic vineyard, says that if the field can deliver just one successful new pharmaceutical, that alone could open "a floodgate of interest" in the field. Jaouen agrees, noting that the new discipline needs to prove it can create "something useful for society."

Because bioorganometallic chemistry had never been the focus of an international conference, Jaouen, Fish, and their colleagues decided to organize one. The 1st International Symposium on Bioorganometallic Chemistry took place July 18–20 at ENSCP. It drew about 120 participants from 25 countries, most of them in Europe.

According to all accounts, the conference was a resounding success. Besides offering a showcase for important research being conducted at the interface between organometallic chemistry and biology, the meeting also afforded attendees many opportunities for informal discussions, socializing, and even sightseeing. "Extracurricular" activities included a wine and cheese party, an exclusive organ concert at a nearby church, and a banquet aboard a cruise ship that slowly sailed along the Seine River past the Eiffel Tower and other magnificent landmarks of Paris.

The scientific program of the conference was similarly impressive. The proceedings began with a keynote lecture by Jaouen, who described the efforts of his coworkers, particularly Siden Top and Anne Vessières, to exploit organometallic chemistry in the search for new treatments for breast cancer. Breast cancer is the most common cancer among women; as Jaouen noted, it affects about one in eight women.

The primary drug used to treat the disease is tamoxifen. Although tamoxifen is generally well tolerated, it does have troublesome side effects and other drawbacks. For example, resistance to the drug can develop during long-term therapy. Tamoxifen also increases the risks of endometrial (uterine) cancer and blood clotting in the lungs, according to Jaouen. And it's not effective against hormone-independent tumors, which account for about one-third of all breast cancer cases.

The way tamoxifen works is not yet fully understood, but its main function is to block or interfere with the action of estradiol, one of the class of female hormones known as estrogens. Under certain conditions, the binding of estradiol to an estrogen receptor inside the nucleus of a breast cell can initiate a process that leads to the growth and proliferation of the cell--a hallmark of cancer. When tamoxifen, in the form of its active metabolite, hydroxytamoxifen, binds to an estrogen receptor instead of estradiol, the cell is not activated to grow and divide.

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	ANTIESTROGENIC In hydroxy-ferrocifen, the -phenyl group (red) of hydroxytamoxifen has been replaced with a ferrocenyl group, which has slightly greater bulk and lipophilicity.

THE SITUATION is complicated by the fact that there are two known estrogen receptors (ER and ER), and they act via different mechanisms. ER is believed to be involved in the proliferation of tumors that respond to tamoxifen, while ER is thought to be implicated in the proliferation of tumors that don't respond to the drug.

In trying to find better alternatives to tamoxifen, Jaouen and coworkers have investigated tamoxifen analogs that contain an organometallic moiety. The discovery that certain inorganic complexes such as cisplatin, Cl₂Pt(NH₃)₂, are effective against testicular cancer has led to increased research on metal complexes as antitumor agents, according to Jaouen. Some cyclopentadienyl (Cp) metal complexes, such as titanocene dichloride (Cp₂TiCl₂), have shown particular promise in early trials, so Jaouen decided to see what effect such metallocenes would have when they're attached to tamoxifen or hydroxytamoxifen.

As Jaouen reported in Paris, the Cp₂TiCl₂-tamoxifen hybrid took three years to synthesize and turned out--surprisingly--to behave like an estrogen, strongly promoting the growth of breast tumors [J. Organomet. Chem., 643–644, 350 (2002)]. "So we will have to forget the use of titanium" to treat breast cancer, he remarked.

The results with ferrocene-substituted tamoxifen analogs--"ferrocifens"--also were surprising, but in a decidedly upbeat way. The Paris researchers studied the effects of several hydroxy-substituted ferrocifens on the proliferation of two lines of breast cancer cells, one used for tumors mediated by the ER receptor, and one used for tumors mediated by ER. Three of the ferrocifens exhibited a strong antiproliferative effect in both cell lines, while hydroxytamoxifen, as expected, was effective only against the cells having the ER receptor [J. Organomet. Chem., 637–639, 500 (2001)]. Ferrocene by itself had no effect.

The ferrocifens, Jaouen pointed out, are the first molecules shown to be active against both hormone-dependent and hormone-independent breast cancer cells.

The mechanisms of their action aren't yet fully understood. But recent studies indicate that the ferrocifens, "like their purely organic equivalents, act by changing the conformation of the receptor protein," according to Jaouen. In addition, when ferrocifen binds to ER, an "oxidant/antioxidant" mechanism may come into prominent play. The ferrocifen-ER complex is thought to dimerize and attach itself to a particular region of DNA. And Fe²⁺ complexes are known to be oxidized to Fe³⁺ by O₂, leading to the generation of highly reactive OH radicals. Jaouen suggests that these radicals could damage the DNA strand close to the binding site, thus explaining the observed antiproliferative effect in connection with the ER receptor. His group has, in fact, observed DNA damage produced by exposure to ferrocifens.

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In other experiments, Jaouen and his collaborators have observed that hydroxyferrocifens strongly inhibit the proliferation of kidney cancer and ovarian cancer cells and have a lesser but still significant antiproliferative effect in endometrial and prostate cancer cells. By contrast, hydroxytamoxifen is inactive in these types of cells.

Furthermore, tests in live rats and mice have revealed that one of the most active hydroxyferrocifens exhibits less acute toxicity than tamoxifen.

The evaluation of these compounds as potential anticancer agents has just begun, Jaouen told meeting attendees. His hope is that they might provide "a much-needed treatment for tumors that are resistant to tamoxifen."

The use of organometallic compounds as potential antitumor agents also is being investigated by Domenico Osella, a chemistry professor in the department of advanced sciences and technology at the Università del Piemonte Orientale "Amedeo Avogadro" in Alessandria, Italy. Osella focused his talk on a new class of metal-based compounds that function by inhibiting telomerase, an enzyme that has been shown to be involved in the proliferation of malignant tissues.

During each cycle of cell division, the telomeres--the protective caps on the ends of chromosomes--are shortened to ensure that after about 50 to 70 rounds, the cell ceases to divide and succumbs to programmed cell death (apoptosis). Telomerase enables tumor cells to circumvent this normal process by elongating and stabilizing the length of the telomeres. The cells thus escape senescence and become immortal. For this reason, "telomerase represents an ideal target for a selective anticancer approach," according to Osella.

He noted that cisplatin's spectacular efficacy against testicular cancer is believed to be due, in part, to telomerase inhibition. Unfortunately, the drug's action is not specifically directed against telomerase, resulting in severe side effects. To minimize this downside, Osella pointed out, it's crucial that the general (nonspecific) cytotoxicity of an antitumor agent be "very modest" relative to its inhibitory effect on telomerase.

HE PRESENTED preliminary results suggesting that triosmium complexes may fit the bill. These compounds consist of a nucleobaselike ligand and a phosphine or phosphite ligand able to impart water solubility, both coordinated to a massive, chemically inert triosmium-nonacarbonyl-hydrido core, (µ-H)Os₃(CO)₉. These compounds differ from platinum(II)-based drugs, Osella said, because they do not alkylate DNA and "can interfere with the catalytic activity of the enzyme by virtue of their steric bulk."

The triosmium compounds were synthesized by chemistry professor Edward Rosenberg and postdoctoral fellow Fabrizio Spada at the University of Montana, Missoula. Osella's group, in collaboration with Donato Colangelo of the medical sciences department, tested them in vitro for telomerase inhibition and cytotoxicity. The best results so far have been obtained with a compound containing both a 3-aminoquinoline ligand and a phosphine ligand carrying three negatively charged sulfonate moieties. It showed good telomerase inhibition (up to 58% inhibition at a concentration of 10²⁵ M) with little evidence of any nonspecific cytotoxicity, suggesting it interacts directly with the enzyme. After several replication cycles, cells exposed to this compound showed evidence of apoptosis and died.

Further studies of the biological properties and mechanisms of action of the 3-aminoquinoline complex and related triosmium compounds are ongoing.

Cancers are not the only diseases that might be treatable using organometallic pharmaceuticals. Chemistry professor Jacques S. Brocard of the University of the Sciences & Technologies of Lille, in Villeneuve d'Ascq, France, and his colleagues have targeted malaria. Several drugs, such as chloroquine, are used against the malaria parasite, Plasmodium falciparum, but resistance to these drugs is increasing.

Since the parasite needs iron for its development inside the red blood cell, Brocard and coworkers decided a few years ago to try a simple strategy: combine poison (chloroquine) and bait (ferrocene) in the same molecule. They inserted a ferrocenyl group into the side chain of chloroquine, thus producing a hybrid compound called ferroquine that is much more potent in mice than chloroquine [Parasitol. Res., 87, 239 (2001)].

Tests have shown that ferroquine is active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium and that it is safe and effective in mice, as well as being nonmutagenic. Even when resistance to the drug builds up in mice, Brocard pointed out, it can be reversed. Thus, he believes the compound is a good candidate for further development. But so far no development deal has been struck, he told his listeners, because pharmaceutical firms have shown "little eagerness to invest in drugs intended for developing countries."

One shining example of an organometallic pharmaceutical that has been successfully commercialized is technetium-99m sestamibi, a hexakis(alkyl isocyanide) complex of ^99mTc(I) that has become the most important myocardial imaging agent. The success of this compound, known by its trade name Cardiolite, has inspired researchers to develop other ^99mTc-based radiopharmaceuticals, according to Roger Alberto, a professor of inorganic chemistry at the University of Zurich.

But as Alberto pointed out at the Paris symposium, ^99mTc complexes used for diagnostic imaging are different from most other bioorganometallic compounds in that they have to be prepared in water from the readily available precursor, [^99mTcO₄]². Medical personnel must synthesize the imaging agent quickly because ^99mTc has a half-life of about six hours. The preparative reaction also needs to be quantitative and simple to carry out, with the product solution ready to inject into the patient.

	Alberto PHOTO BY RON DAGANI

ALBERTO'S RESEARCH has been aimed at finding more convenient methods for preparing technetium precursor complexes and attaching them to particular biomolecules. A few years ago, for example, he and his colleagues developed a method for directly converting [^99mTcO₄]^- into [^99mTc(OH₂)₃(CO)₃]⁺, which has attracted much interest as a versatile precursor for ^99mTc radiopharmaceuticals [J. Am. Chem. Soc., 120, 7987 (1998)]. This water- and air-stable aquo-carbonyl complex contains three labile water ligands that can easily be substituted with a wide variety of organic ligands, thus providing a family of carbonyl complexes that can be used in life sciences and nuclear medicine applications.

Last year, Alberto and his colleagues reported an improved one-pot synthesis of the ^99mTc aquo-carbonyl complex. The earlier synthesis depends on the use of gaseous carbon monoxide as the source of the CO ligands, making it unsuitable for commercial radiopharmaceutical "kits." In the new synthesis, a saline solution of [^99mTcO₄]^- is treated with the carbonylating reagent K₂[H₃BCO₂] at 90 °C for 10 to 20 minutes, giving [^99mTc(OH₂)₃(CO)₃]⁺ in yields greater than 98% [J. Am. Chem. Soc., 123, 3135 (2001)]. The borano-carbonate reagent not only reduces the Tc(VII) atom to Tc(I), but also serves as a solid, air-stable source of CO.

In further work, Alberto's group has shown that the technetium aquo-carbonyl complex will react in physiological (buffered aqueous) solutions with acidic, water-soluble cyclopentadiene derivatives to furnish technetium half-sandwich complexes. In these complexes, the metal is coordinated to the five carbons of the cyclopentadienide ring and to the three carbonyl groups.

Half-sandwich complexes are of interest for radiopharmaceutical purposes because they can be made from a cyclopentadiene that is attached to a targeting biomolecule such as a tumor-specific peptide or a small molecule that binds to a central nervous system receptor. The targeting molecule ensures that the radioactive metal is transported to the desired tissue. And because the half-sandwich complex is robust and highly lipophilic, it can potentially ferry the radioactive label across the blood-brain barrier.

In one demonstration, the Zurich chemists reacted [^99mTc(OH₂)₃(CO)₃]⁺ in phosphate buffer with a conjugate of cyclopentadiene and the aryl piperazine ligand (R) of a serotonin receptor. The corresponding (R-Cp)^99mTc(CO)₃ complex was produced in quantitative yield. They also demonstrated that the half-sandwich complex can be made in a one-pot synthesis by heating together [^99mTcO₄]^-, K₂[H₃BCO₂], and the R-Cp conjugate in aqueous solution [Angew. Chem. Int. Ed., 40, 3062 (2001)].

The use of ^99mTc in diagnostic medicine takes advantage of its gamma ray emission. But about 20% of the time, the metastable nucleus (hence the "m" appended to the mass number) decays by internal conversion, which leads to the ejection of inner- and outer-shell electrons. These electrons, Alberto suggested in his Paris talk, probably could be used for cancer therapeutic purposes--if the radionuclide can be brought close to a DNA strand.

With this in mind, he and his coworkers are exploring ways to bring ^99mTc complexes into the cell nucleus. For example, they have attached triamines to some well-known DNA intercalators such as anthraquinone, pyrene, and acridine. The triamines form cationic technetium complexes, and the intercalators home in on a DNA strand, inserting themselves between base pairs using -stacking forces. In preliminary studies using calf thymus DNA, Alberto's team has found that the metal complexes bind quite strongly to DNA.

This therapeutic approach will have to overcome many hurdles and potential pitfalls before it is proven successful. Nevertheless, Alberto and coworkers have patented the idea and are pursuing its further development.

Although organometallics in medicine was a major theme of the conference, other aspects of bioorganometallic chemistry also shared the spotlight. For example, Lawrence Berkeley's Fish discussed his group's efforts to overcome the problem of cofactor regeneration in the emerging area of biocatalysis. As he noted in his talk, at least one-third of all known enzymes require the use of cofactors such as NAD⁺ (nicotinamide adenine dinucleotide) and its reduced form, 1,4-NADH, to perform oxidations or reductions. Aside from their importance in biology, such cofactors also can be used in enzymatic processes to prepare chiral molecules that are of interest as pharmaceuticals or specialty organic compounds.

FROM AN INDUSTRIAL perspective, however, these cofactors are not ideal. They are expensive--usually much more so than the products of the enzymatic reaction. Also, NAD⁺ and NADH are fairly complicated molecules, built from sugar, phosphate, and adenine building blocks. Because of their chemical composition, they are susceptible to degradation via hydrolytic reactions, which means they must be replenished, at some expense.

Fish and coworkers wondered whether a stripped-down version of the 1,4-NADH molecule might fool the enzyme into using it as a cofactor in a chiral synthesis. To investigate this question, he and his coworkers first synthesized simpler versions of NAD⁺--in one case, replacing the natural cofactor's sugar, pyrophosphate, and adenine groups with a solitary benzyl group. They then showed that, in aqueous solution, these biomimetic models behave chemically like NAD⁺ in a fundamental catalytic cycle that regenerates 1,4-NADH from NAD⁺. Like NAD⁺ itself, each NAD⁺ model grabs a hydride ion from an organorhodium hydride catalyst, producing a biomimetic version of 1,4-NADH [Inorg. Chem., 40, 6705 (2001)].

In the next step, Fish and postdoctoral fellow H. Christine Lo showed that these biomimetic models of 1,4-NADH interact with the enzyme horse liver alcohol dehydrogenase the way natural 1,4-NADH does: The model compound gives up its hydride ion to the enzyme, with the end result being the enantioselective reduction of a prochiral ketone substrate to a chiral alcohol [Angew. Chem. Int. Ed., 41, 478 (2002)].

The only structural component that both 1,4-NADH models have in common is a dihydronicotinamide moiety, and clearly that is sufficient for the enzyme to recognize the biomimetic compound, according to Fish. The mechanism of the enzymatic reaction, though, remains a subject of debate.

Nevertheless, Fish hopes that these results will pave the way for the use of NAD⁺ model compounds in a variety of biocatalytic processes of industrial importance. If the biomimetic cofactor proves to be sufficiently robust to be used over and over again, there would be no need to constantly replenish it, and that would save money, he said.

Another conference speaker who works on the synthetic front is chemistry professor Karl Heinz Dötz, codirector of the Kekulé Institute of Organic Chemistry & Biochemistry at Rheinische Friedrich-Wilhelms University in Bonn, Germany. Dötz and coworkers have been exploring the use of organometallic carbene complexes in the synthesis of carbohydrates. They start out by functionalizing the anomeric carbon (C-1) of sugars with a metal carbene, producing a >C5Cr(CO)₅ moiety, for example. The skeleton of this "sugar metal carbene" is then modified with various reagents, yielding structures that can be difficult to produce via conventional synthetic routes.

IN ONE EXAMPLE Dötz described, he and Ph.D. students Wilm Haase and Christoph Jäkel have developed a sequence that allows them to transform readily available D-sugars into the less common nonnatural L-sugars. They first prepare a chromium carbene furanosylidene complex and treat it with ammonia or a primary amine to stereoselectively open the sugar's five-membered ring, yielding an acyclic aminocarbene complex. This acyclic complex is then recyclized to give the chromium iminofuranosylidene complex, but with inversion of configuration at C-4 [J. Organomet. Chem., 617–618, 119 (2001)]. Pyranosylidene complexes, which consist of six-membered-ring sugars, also undergo this sequence of reactions, which can be performed as a one-pot procedure, according to Dötz.

This transformation is made possible by the strongly electrophilic carbene carbon, which readily adds nucleophiles such as amines. The electron-withdrawing character of the carbene carbon also promotes other useful reactions, such as photoinduced C-glycosidation. In this reaction, which involves methanol and one of the chromium carbonyl groups, Dötz and Ph.D. student Markus Klumpe found that the sugar's >C5Cr(CO)₅ moiety is transformed into >CH–CO₂CH₃. If, instead of methanol, a sugar with an unprotected hydroxyl group is used, the glycosidation reaction yields a disaccharide.

"In my eyes," Dötz told C&EN, "the message of this work is that organometallic methodology offers opportunities for the stereoselective synthesis and modification of multifunctional natural products such as sugars."

	Severin PHOTO BY RON DAGANI

The organometallic approach also is opening new vistas in the analytical arena, as demonstrated by the work of Kay Severin, an assistant professor in the Institute of Molecular & Biological Chemistry at the Swiss Federal Institute of Technology in Lausanne, Switzerland. In the past three years, Severin and coworkers have shown that half-sandwich complexes can be used as building blocks to construct highly selective ion chelators, or ionophores. Such chelators have potential applications in ion-selective sensors, phase-transfer catalysis, and membrane transport, for instance.

Severin has been particularly interested in developing a chemical sensor for lithium ion because of the importance of lithium carbonate (Li₂CO₃) in the treatment of bipolar disorder, once known as manic depression. Because the therapeutically useful range of lithium concentration in the patient's blood is relatively narrow, he explained in Paris, Li⁺ levels in the patient must be monitored and controlled on a regular basis. This monitoring is currently done using atomic emission spectroscopy, but it could be done more efficiently if a suitable chemosensor were available.

The ideal chemosensor for Li⁺ would be based on an ionophore (receptor) that binds Li⁺ with an extremely high affinity and would be able to distinguish between Li⁺ and Na⁺, which is normally present in blood at much higher levels, Severin pointed out. "You also need to have a way to transduce the lithium-binding event into some kind of signal output."

Researchers have prepared many good Li⁺-binding molecules, but these often have drawbacks such as being difficult and expensive to synthesize. To simplify the synthesis of ionophores, Severin and other chemists have turned to metallomacrocycles that self-assemble in one step from simpler components. Last year, for example, Severin's group reported a family of triangular macrocyclic receptors that form from building blocks derived from 3-hydroxy-2-pyridone and [(-ligand)MCl₂]₂.

A variety of p-ligands--such as pentamethylcyclopentadienide (C₅Me₅²) and benzene--and transition metals such as ruthenium, rhodium, and iridium have been used by the group [Chem. Eur. J., 7, 3197 (2001)].

The macrocyclic receptor consists of three half-sandwich moieties [(-ligand)M] linked by three bridging, tridentate ligands (the pyridonate dianion). At the core of this macrocycle is a small cavity ringed by three oxygen atoms that turns out to be a good binding site, Severin pointed out. On addition of either NaCl or LiCl to several of these receptors, the alkali metal ion becomes strongly bound to the oxygen atoms of the cavity, giving an extremely stable host-guest complex in quantitative yield. K⁺ and larger ions don't bind because they are too big to enter the cavity.

Severin said it's possible to make receptors that are completely selective for Li⁺ ion by changing the size of the -ligand or altering the electronic nature of the receptor. However, he admitted, "the best lithium receptor we have so far was discovered more or less accidentally." In an effort to prepare receptors with six chelating oxygen atoms, he and his coworkers synthesized a ruthenium macrocycle incorporating ethyl benzoate as the p-ligand. The carbonyl moiety of this ligand, they expected, would provide three additional oxygen donor atoms to coordinate to the bound metal ion. However, an X-ray crystal structure of the host-guest complex revealed that those carbonyls point away from the metal cation and do not participate in its binding.

Nevertheless, this receptor is highly proficient at binding LiCl as an ion pair. According to Severin, LiCl is very difficult to extract from water because of the high enthalpy of hydration of Li⁺ and Cl^-. But with this receptor, he reported, "we are able to selectively extract LiCl from aqueous solution containing large amounts of other metal salts. The selectivity is so high that we are even able to detect a small amount of lithium ion in an aqueous solution that is saturated with sodium chloride" [Proc. Natl. Acad. Sci. USA, 99, 4997 (2002)]. Few, if any, other synthetic ionophores can match this performance, he believes.

Severin and coworkers have demonstrated that the presence of a bound ion in the receptor cavity can be detected either electrochemically or with a simple colorimetric test. He is currently collaborating with an electrochemistry group at the Lausanne institute to construct a functional sensor based on a Li⁺ receptor.

In his talk, Severin also discussed the concept that a macrocyclic receptor containing a bound Li⁺ ion would bind fluoride anion and thus could be used as a specific sensor for fluoride ion if the opening of the cavity were small enough to keep larger anions from entering. Their investigation of this possibility was prompted by the unusual binding behavior of a macrocycle containing three (C₅Me₅)Ir units that was synthesized in Severin's lab by graduate student Marie-Line Lehaire. When this macrocycle, in acetonitrile solution, is treated with LiCl, the LiCl adduct forms extremely slowly compared with other Li⁺ ionophores because the C₅Me₅ ligands are so effective at shielding the binding site from intruders. It thus seemed to be a good candidate for a highly selective fluoride ion sensor. Indeed, when the LiCl adduct is treated with KF, a Cl-F anion exchange occurs, producing the LiF adduct, which can be detected electrochemically [Angew. Chem. Int. Ed., 41, 1419 (2002)].

According to Severin, this LiF adduct appears to be the first complex of molecular LiF to be structurally characterized.

IN ADDITION, he noted, the triiridium receptor can even be used to determine fluoride ion in protic solvents such as water or methanol--a claim that cannot be made for the vast majority of fluoride sensors reported in the literature.

Severin, who received his Ph.D. in chemistry in 1995, represents the new generation of organometallic chemists, while his former thesis adviser--Wolfgang Beck of Ludwig Maximilians University in Munich, Germany--represents the generation that first explored the bio side of organometallic chemistry. Beck, who at 70 is retired from research but is still publishing papers, attended the Paris conference, where he received the first Lavoisier Medal of the International Symposium on Bioorganometallic Chemistry. This prize was established by the conference organizing committee "to recognize the pioneers and major contributors to the field," according to conference chairman Jaouen.

Beck's "superb studies," such as his synthesis of the first metal carbonyl complexes of nucleobases and amino acids, "provided the essential link between organometallic and bioorganometallic chemistry," Jaouen noted during the award presentation.

The awarding of this first prize in bioorganometallic chemistry suggests that further prizes and conferences in this series are in the offing. And that is indeed the case, as Zurich's Alberto made clear at the conclusion of the conference. Zurich, he said, will be the venue for the next conference, in July 2004. And, he added, "it will be quite a challenge to compete with [this] first meeting," which he critiqued as "very successful" and a great learning experience.

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