Pro-DPH rapidly converts to DPH in plasma3 at 37° C.

Micrograms per ml., DPH equivalents

Diphenylhydantoin £H

10 20 30 60 Incubation time (minutes)

a Rat plasma plus pH 7.8 phosphate buffer.

DPH as such in the U.S. may not be large enough to make the rigors and expense of a New Drug Application with the Food and Drug Administra­tion feasible. And pro-DPH does have drawbacks. For one thing, according to estimates made by Dr. Stella, it costs about five times more to make pro-DPH than it does to make DPH, and the acute toxicity of pro-DPH is great­er than that of DPH by intravenous administration.

Dr. Higuchi, however, is confident enough in the prodrug concept to form a curious corporate entity (with the University of Kansas holding 40% of the company's stock) to capitalize on still embryonic technology. The com­pany, INTERx Research Corp., is locat­ed in a building on the University of Kansas campus in Lawrence. Dr. Higu­chi is president and chairman of the board. At INTERx, which holds the patent on pro-DPH, work on other pro­drugs is in progress including a pro-digoxin for cardiac insufficiency and a pro-antimalarial that is about 10,000 times more soluble than a promising compound developed by Walter Reed Army Institute of Research.

Chlorofluorocarbons threaten ozone layer

168TH rfCS

Because of their inertness in ordinary chemical reactions, chlorofluorocarbons may be finding their way through the lower atmosphere to the stratosphere where they threaten to catalyze decom­position of the earth's protective ozone layer, according to physical chemists from the University of California. Once these compounds diffuse into the ozone layer, decomposition reactions releas-

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CIRCLE 18 ON READER SERVICE CARD

Sept. 23, 1974 C&EN 27

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ing chlorine atoms from the com­pounds could initiate a chain reaction "quite analogous to nitrogen oxides" for the decomposition of ozone, the chemists told the Division of Physical Chemistry.

Further, since chlorofluorocarbons have only been manufactured since 1930 and estimates of the time needed for these molecules to diffuse to the ozone layer range from 20 years to 40 to 50 years, depending on the model for atmospheric diffusion used, the total effect of chlorofluorocarbons already in the atmosphere will not be felt for some time. "We think that the risks that are involved . . . are too large for us to continue this, and that we ought to discontinue putting chlorofluorocar­bons into the atmosphere," concludes Dr. F. Sherwood Rowland of the Uni­versity of California, Irvine.

The ozone layer, which surrounds the earth about 25 km. above its sur­face, absorbs strongly in the ultraviolet region, thus shielding the lower atmo­sphere and the earth's surface from higher energy radiation. Solar radiation interacts with naturally occurring oxy­gen molecules to form ozone at this al­titude as well as with the ozone itself to destroy it. The result is believed to be a stable natural concentration of the molecule in the stratosphere.

But several catalytic decompositions of ozone are known, and there has been

considerable concern in recent years that some of these catalysts might be entering the stratosphere, causing a net depletion of the ozone concentration there. Concern has focused most re­cently on the effect of nitrous oxides released into the stratosphere by flights of supersonic transport aircraft and of fallout from nuclear explosions in the atmosphere.

In connection with the supersonic transport, the National Academy of Sciences has estimated that a 10% de­crease in the ozone layer would cause an increase of 8000 cases per year of skin cancer among the white popula­tion of the U.S. The Climatic Impact Assessment Program, set up to study the effects of the supersonic transport, estimates an even more pronounced ef­fect—an increase of 8000 skin cancer cases per year for a 1% decrease in the ozone layer, and an essentially linear increase beyond that level, according to Dr. Rowland. The ozone layer also serves to warm the upper atmosphere and may have far-reaching effects of global climate and weather patterns.

Concern that chlorofluorocarbons might cause depletion of the ozone layer comes from the extreme inertness of these compounds to ordinary chemi­cal reactions. More than 1 million tons of each of the two most important compounds of the class—fluorocarbon-11, CFC13, and fluorocarbon-12,

Rowland: decomposition of ozone

CF2CI2—are produced annually for use as refrigerants and as propellants in aerosol sprays. Extensive investigations conducted by the California Statewide Air Pollution Research Center under Dr. James N. Pitts, Jr., and other groups have not found any biological or photochemical decomposition reactions of these compounds occurring in the lower atmosphere. A rough calculation made by Dr. James E. Lovelock of the University of Reading, England, based on atmospheric concentration data for 1972 indicates that all the fluorocar-bon-11 produced up to that time could be accounted for in the lower atmo­sphere.

If these compounds do not decom-

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28 C&ENSept. 23, 1974

pose in the lower atmosphere, eventu­ally all chlorofluorocarbons produced will find their way into the strato­sphere, the California chemists reason. There two known decomposition reac­tions occur. The first is reaction with the electronically excited oxygen atom, O^D), which is formed by ultraviolet bombardment of oxygen atoms and ex­ists in low concentration in the upper portion of the ozone layer and above. The second decomposition reaction is direct interaction of the fluorocarbons with ultraviolet radiation above the ozone shield. In either case, the prod­uct is a free chlorine atom that attacks ozone in a two-step reaction, trans­forming one atom of oxygen and one molecule of ozone into two oxygen mol­ecules, while regenerating the chlorine catalyst.

Dr. Pitts, Dr. Roger Atkinson, and Dr. Hugo L. Sandoval of the University of California, Riverside, investigated the reaction of five common chlorofluo­rocarbons with excited oxygen to deter­mine the probable half-lives of these compounds in the stratosphere, assum­ing no competition from other decom­position reactions. These half-lives range from about 100 years at 20 km. above the earth to one year at 40 to 50 km., leading Dr. Atkinson to conclude that this reaction is probably a signifi­cant decomposition pathway for these chlorofluorocarbons in the stratosphere but not as important as direct photo-dissociation.

Dr. Rowland and Dr. Mario J. Moli-no projected buildup of fluorocarbons in the stratosphere for the next 50 to 80 years and their effect on the ozone layer, assuming that direct photodisso­ciation of these compounds is the only important decomposition mechanism. They used previously developed atmo­spheric diffusion models to examine three possible chlorofluorocarbon pro­duction patterns: all production stop­ping immediately, production held constant at current levels for 15 years and then stopping, and production continuing to increase at the present rate of 10% per year for 15 years and then stopping entirely.

In all of these models, Dr. Rowland and Dr. Molino find that present ef­fects on the ozone layer, a 1% decrease by their estimates, are minor compared to what is expected in the future. The maximum effect probably will occur 50 to 80 years from now and remain rela­tively acute for a long period; by one model, chlorofluorocarbon concentra­tions would remain above their half maximum value for more than a century after surface release of the chemicals ends. Using the highest production model, they predict a 10% decrease in the ozone layer 50 years from now.

These predictions assume that even­tually long-lived gaseous molecules such as the chlorofluorocarbons diffuse into the stratosphere. Whereas there is extensive evidence that these materials continue to build up in the lower at-

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Sept. 23, 1974 C&EN 29

mosphere as production continues, there is very little scientific informa­tion about their presence in the strato­sphere, according to Dr. Rowland. A recent study conducted by the Atomic Energy Commission for the National Oceanic and Atmospheric Administra­tion suggests that there are detectable amounts of chlorofluorocarbons in the stratosphere that are not incompatible with certain atmospheric diffusion models, according to Dr. Lester Mach-ta of NOAA's Air Resources Laborato­ry. It is impossible to determine whether this concentration is increas­ing from these data, however.

Conef lower yields third useful compound

168TH ACS ΓΝΙΟΝΜ. m€€TIMG

A third compound, one with juvenile hormone mimicking activity, has been discovered in the roots of the American coneflower, Echinacea angustifolia DC (family compositae), adding to two found earlier that have potential value as pesticides and antitumor agents. As yet, however, possible use of the chem­icals is limited by deficiencies in prop­erties.

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Termed a "pesticidal cornucopia" by Dr. Martin Jacobson of the U.S. De­partment of Agriculture's Agricultural Research Service the American cone-flower, a perennial, is considered a common weed in the central U.S. Some of its parts have been known by various Indian tribes to have antiseptic and analgesic properties. For a time, the dried rhizome and roots, and their alcoholic extracts, were dispensed by early pharmacists as analgesics and as medicines for treatment of bronchial disorders.

Following studies by various other groups, some chemists headed by Dr. Jacobson began working with coneflow­er root several years ago while looking for an alternate source of pyrethrin (other than imported pyrethrum flow­ers) for use as an insecticide. Having heard that coneflower root was said to have a numbing effect on the mouth— the same action as pyrethrin—the USDA scientists obtained a compound from dried coneflower roots in 0.01% yield. They identified the structure of the compound and named it "echina-cein." It is highly toxic to the adult housefly, Culex mosquito larva, and German cockroach.

The compound is unstable in air, po­lymerizing after an hour at room tem­perature, Dr. Jacobson told the Divi­sion of Pesticide Chemistry. In nitro­gen, it will polymerize in two days but is stable in hydrocarbon solution at 5° C. for several months.

Although the compound has insecti-cidal properties, if used as a spray, it is an irritant to the human nose and throat. Thus, to use echinacein as an insecticide, its instability and irritating properties must be overcome by suit­able formulation or by chemical modi­fication of the molecule, Dr. Jacobson points out.

In 1972 another compound, obtained from coneflower roots in 0.24% yield, was identified by Dr. Jacobson and co­workers. It has no insecticidal proper­ties but has caused regression in cer­tain tumor systems, although it is in­active with others. The oncolytic activity of the compound is low, but the substance might be a promising lead to synthesis of more active com­pounds, especially since a diene olefin hasn't previously been reported to show antitumor activity, Dr. Jacobson says.

Recently the third material, not yet positively identified, has been obtained from coneflower roots by the USDA group using solvent partition and chro­matographic methods. It shows high juvenile hormone mimicking activity in the yellow mealworm, preventing the molting of pupae to the adult stage. Dr. Jacobson believes it has consider­able promise in insect control. It is ob­tained from dry roots in 0.0003% yield.

Based on infrared, nuclear magnetic resonance, mass spectral, and ozonol-ysis techniques, the compound has been tentatively identified as D-10-hy-

Coneflower root compounds exhibit unusual activities

M

Echinacein, (E,Z,E,E)-/V-isobutyl-2,6,8,10-dodecatetraenamide, is toxic to houseflies, mosquito larvae, and German cockroaches, but has drawbacks in other properties

(Z)-1,8-pentadecadiene shows a low level of antitumor activity

OH D-10-hydroxy-4, 10-dimethyl-(E)-4, 11-do-decadien-2-one shows high juvenile hor­mone mimicking activity in yellow meal­worms

droxy-4, 10-dimethyl-(E)-4,ll-dodeca-dien-2-one. The proposed structure for the compound is quite similar in physi­cal and chemical properties to those of nerolidol, a natural substance used in perfumery, Dr. Jacobson says, but nerolidol is nearly without juvenile hormone mimicking activity.

Technique probes astatine reactions

168TH AG mom. meeTiNG

Radiochemical techniques are moving into new areas of experimentation. Use of short-lived radioactivity to measure reactive scattering in crossed molecular beams has led to the first identification and measurements of elementary reac­tions involving astatine. The work was carried out at Brookhaven National Laboratory by Dr. J. Robb Grover and Dr. Charles R. Iden and their cowork­ers.

The results come from efforts to take advantage of the great sensitivity for detection of neutral atoms and mole­cules when radioactive elements are used in experiments. For a given ex­periment, maximum sensitivity theo­retically occurs when the half-life is 10- 5 to 1 0 - 1 second, optimum for crossed-beam measurements, according to Dr. Iden. He described the tech­nique for the Division of Nuclear Chemistry and Technology, and Dr. Grover discussed experimental results for the Division of Physical Chemistry.

For their work, the chemists chose

30 C&ENSept. 23, 1974

ABBOTT