NONOates are complexes of nitric oxide and a nucleophile The NONOates possess activity in a number of biological assays, Keefer says. -N- •N=0 Their activity is a function \ of the amount of nitric oxoide generated over the Diethyl amine NONOate length of the experiment. The experiments suggest H 2 N-{CH 2 ]3-NH 2 -(CH 2 )3-CH 2 that "factors such as metab\ N—N—N=0 olism appear to play no sigH2N-{CH2VCH2 V nificant role in the expression of these compounds' Spermine NONOate activity," he says. The utility of the NONOates is suggested by the rebeen known since 1799, Keefer notes. sults obtained for the diethyl amine "Despite that knowledge, the chemis- NONOate (DEA/NO) and spermine try of these complexes has remained NONOate (SPER/NO). DEA/NO has a largely unexplored/' he says. two-minute half-life in buffer at physioInspired by the discoveries of Russell logical pH; SPER/NO has a 40-minute Drago and coworkers in the 1960s, half-life. In both in-vitro and in-vivo asReefer's group studied adducts of nitric says, DEA/NO's biological activity is exoxide and a number of amines in the erted rapidly and then disappears. By early 1980s, demonstrating that they are contrast, SPER/NO's biological activity stable solids that spontaneously release takes much longer to peak, and then denitric oxide when they are dissolved. clines slowly. This suggests to Keefer The work "wasn't biologically interest- that NONOates can be readily tailored ing in 1982," he says, but, with the dis- to specific medicinal applications. covery of numerous physiological roles "Essentially, the first five we pulled for nitric oxide, "it is, now." Keefer points out that a great deal of effort is being expended on finding ways to reduce nitric oxide concentrations in organisms to eliminate its toxic effects. The cardiovascular collapse associated with toxic shock, for example, ultimately is mediated by a huge exA S H I N G T O N , IXC. cess of nitric oxide that causes relaxation of smooth muscle in the walls of blood vessels and severe hypotension. Spurred by environmental concerns, Not enough attention is being focused the National Science Foundation has on methods of raising levels of nitric ox- designed a new program to support ide in tissues, Keefer believes. Com- pre-competitive research projects in pounds that could do this could find use chemistry and chemical engineering in treating high blood pressure, inappro- aimed at reducing pollution at its priate blood clotting, impotence, and source. Called the Benign Chemical many other disorders. For this reason, he Synthesis & Processing Program, it got and colleagues Danae Christodoulou, under way earlier this year, and its Tambra M. Dunams, Joseph A. Hrabie, progress so far was detailed for the DiChris M. Maragos, Joseph E. Saavedra, vision of Petroleum Chemistry by Kenand David A. Wink have been exploring neth G. Hancock, director of NSF's the fundamental chemistry of NONO- chemistry division. ates for potential use in biomedical reAt the crux of environmental probsearch. Some scientists, Keefer says, be- lems in the U.S. is a concern that ecolieve that agents such as nitroglycerin nomic growth and environmental qualand sodium nitroprusside are adequate ity are now both at risk. The NSF prodeliverers of nitric oxide. Keefer, howev- gram, Hancock explains, is seen as at er, disagrees. Most such agents do not least a small step toward addressing release nitric oxide spontaneously, but some parts of that concern. Sponsored require some form of metabolic or elec- by NSF's divisions of chemistry and of tron transfer activation. This need limits chemical and thermal systems, the protheir utility, he argues. gram is being carried out in concert CH3CH2
y
off the shelf for our studies were chosen for their structural and physicochemical diversity," Keefer says. "Nevertheless, a couple of them have potencies comparable to clinical agents now in use, which I think is remarkable. Our results suggest that we already have reasonable candidates for drug development." The Frederick researchers are currently focusing on creating NONOates with longer half-lives and on developing methods for localizing NONOates in specific tissues or organs. For example, Keefer reported that his group has developed polymer matrices containing NONOates. In one strategy, a NONOate is dispersed throughout the matrix. In another, the NONO" group is attached directly to the polymer backbone or to polymer side chains. These polymers release nitric oxide and possess biological activity in in-vitro assays. The researchers are investigating the biological utility of these polymeric NONOates. Keefer also plans to continue to investigate nitric oxide genotoxicity. Rudy Baum
NSF grant program aims to reduce pollution
^i^i^i^t?
with the Council for Chemical Research (CCR). Addressing the rationale for the program, Hancock notes that chemists have made laudable contributions to the high standard of living in the U.S. and to national trade—but they have also contributed to environmental problems. Chemists, he says, have many pragmatic reasons to be concerned with the environment, but there is a more urgent moral imperative: the responsibility to preserve the environment and a fair share of its nonrenewable resources for future generations. The program focuses on fundamental research in chemistry and engineering that will lead to discovery and development of advanced, environmentally benign methods of chemical synthesis and processing in industry. Industry is already involved in such work in its own interests—for example, to minimize waste and emissions for economic reasons. No fundamental research is needed here, Hancock says. Similarly, research in such areas as those of remediation or tracking and monitoring the fate of chemicals in the SEPTEMBER 14,1992 C&EN
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environment is already supported by other agencies. Rather, the joint initiative between NSF and CCR intends to finance longrange research supporting new synthetic methodologies, novel process designs, and process improvements that would reduce the potential for environmental release in the first place. Projects are being sought that would lead to feedstock substitutions, alternative synthetic and separation procedures, and more specific and efficient catalysts and catalytic processes that would minimize by-product formation and reduce waste at the source. Some of the general areas that have been targeted (the program is not restricted to them) are as follows: • New chemistries and methodologies for on-demand, on-site production and consumption of chemical synthesis intermediates. • More highly selective catalysts. • Low-energy separation techniques. • Syntheses that bypass toxic feedstocks and solvents. • Better membrane or molecular sieve technology that integrates transport and reactions. • New processing methods that eliminate hard-to-entrap, micron-sized aerosols. • Alternative syntheses that eliminate or combine process steps. Hancock notes that some progress has been made in these areas in industry—for example, the replacement of solvents with water in some areas of pharmaceutical manufacture and the replacement of caustic cleaners with vibratory methods in electronics manufacture. Projects of interest for the new program must show appropriateness to current national concerns for pollution reduction and prevention. Vague arguments that the proposed research may eventually reduce pollution are not compelling. Even so, the research must be fundamental in nature—that is, NSF is seeking innovative and high-risk/ high-payoff ideas. The foundation does not invite studies of the problem but is seeking more specific approaches to solutions. The idea is to prevent pollution, not to improve waste treatment. The program will encourage interdisciplinary interactions of all kinds. Industrial participation is a requirement. The partnership should be of an intellectual 34
SEPTEMBER 14,1992 C&EN
nature to ensure relevance to an industrial setting. Financial participation and other services are clearly welcomed but not required. CCR has agreed to act as the broker in the program. It will assist university researchers in developing necessary liaisons with industry. Member companies in CCR will also generate idea lists and possible generic projects that are ripe for collaboration. Hancock says that the range of these lists is impressive. At the beginning of the program earlier this year, most of the original proposals were in areas of chemical engineering. About $1 million in awards have been made to date. Although, clearly, chem-
ical synthesis is at the center of the program, the challenges are of greater scope. Appropriate chemistry is also applicable to improved detection, monitoring, and separation of pollutants and to the utilization of by-products. NSF and the Environmental Protection Agency will cooperate closely, Hancock says. But EPA's mission is strictly regulatory, and its research program reflects this. Funding specifically for the new program has been requested from Congress in the President's budget to move the program beyond the few projects that have been supported so far. Joseph Haggin
Test of enhanced electronic journals begins In a development that points the way toward the future of information delivery to the scientist's desktop, Cornell University chemists are gaining access to an electronic version of 20 American Chemical Society journals. Beginning this month, the chemists will be able to see all of the text, figures, photos, tables, and equations from one year's issues of the journals, using computer terminals in their own offices and labs. The scientists are helping to evaluate the overall usefulness of the prototype system, and will also test different interface options for presenting the journal data.
The system—called the Chemistry Online Retrieval Experiment (CORE)—is a collaborative project among ACS and its Chemical Abstracts Service Division; Bell Communications Research (Bellcore, the research arm of the regional telephone operating companies), Morristown, N.J.; Online Computer Library Center (OCLC, a database resource service for libraries), Dublin, Ohio; and Cornell University's Mann Library. CORE will provide two modes of information presentation. The first consists of "reconstructed" pages that combine machine-readable text with separate scanned graphics images. This
Reconstructed page format on CORE system provides separate windows for document text, figure captions, graphic images, and other elements of journal articles
