Green plants use "primitive immune systems" to protect themselves Green plants, faced continually with insult and injury from invaders such as fungi and insects, have developed what some scientists call "primitive immune systems." Though molecular details of the defense systems of plants aren't much like those found in animals, the two biological kingdoms don't differ much in overall strategies of defense. Perhaps the outstanding difference is that plants apparently lack the complex family of specialized tissues and cells found in animal immune systems. Plants also lack antibodies as such, but some green plants contain a defense system with peculiar parallels to those immune components. Another parallel is that many plants can release noxious chemicals at the site of an injury (C&EN, Sept. 8, page 42)—a behavior that is amazingly like the response, say, in human skin to an insect bite or sting. But it is a protease-inhibitor-based plant defense system that invites more and more comparison to the antibody system in higher animals. The plant system, described largely by agricultural chemist Clarence A. Ryan and his colleagues at Washington State University,
But the same principles that enabled them, and now hundreds of other research teams, to put together antibody-producing cells now are being applied to other cell fusions. Thus, the Hellstrôms have made cell fusions that make specific Τ cell blocking factors. Other research groups are making such hybridomas that make factors capable of exerting just the opposite biological action. Thus, for example, some Τ cells can be grown (as hybridomas) in vitro and can make theoretically limitless supplies of specific toxic factors. With appropriate manipulations, that specificity can be directed at partic ular tumor cells. "It's not clear yet that just because such cells can kill tumors in vitro they'll work in the body or in people," one scientist cautions. But the availability of such cells rejuvenates an old stratagem for fighting cancer, and puts it on an en tirely new footing. Similarly, macrophage and natural killer cells also can be grown in vitro as hybridomas. Except for the need for and the expense of certain growth factors, such cells can be made in unlimited quantities. But no one can predict whether their vitality—and their specificity—will survive the transfer into the real battlefield of the body. Such strategies that pit specific components of the immune system 22
C&EN Sept. 22, 1980
Pullman, is capable of a systemic re sponse to environmental injury, meaning that tissues some distance from the damaged site are orchestrated during the plant's response. The overall response, which can occur in familiar vegetable plants such as corn and potatoes, is the elaboration of several types of proteins that are themselves inhibitors of proteolytic enzymes. Such enzymes typically are part of a grazing insect's digestive sys tem. Thus, if such a predator's digestive system is gummed up by the plant's in hibitors, the insect is deterred from eating and further damaging the plant, and the plant's defense mechanism can be credited with success. Ryan and his colleagues find that plants initially rely on an internal sig naling process before they make the protease inhibitors to cope with insect and other injuries. The signal is con veyed by molecules called PIIF, for protease inhibitor inducing factor. PIIF not only turns on the synthesis of such inhibitors locally where damage occurs, but it can travel through the vascular system of a plant to trigger inhibitor synthesis in distant leaves—as if in an-
ticipation of the flitting nature of insect attack. Recently, the Washington State group found that PIIF apparently is a molecular fragment of the plant cell wall, which is made up of complex sugars. The finding is remarkable inasmuch as most sci entists have considered that the plant cell wall serves a strictly structural role, conferring rigidity along with limited permeability to the environment of a cell. But attributing the PIIF role to a cellwall fragment amounts to putting that molecule (or molecules; the Washington State group says that an array of similar but unidentical fragments act as PIIF) into the same category as hormones: secreted molecules that trigger physi ologic activities at sites distant from where they're released. The plant system is somewhat more complicated even than that. Initial injury liberates PIIF indirectly. The factor is not dispensed until after enzymes are re leased from the vacuoles (special compartments) in the injured cells so that the enzymes then are free to digest the PIIF material away from the now breached cell wall.
against tumor cells aren't really ready larly the large group under Good's yet for clinical application. Success direction at Sloan-Kettering, also are will hinge on achieving a better un pushing bone marrow transplant derstanding of the immune system's technology beyond its present peculiar code, which so often shuts off limits. the destructive forces and permits "I'm sure that this is just a begin tumor cells to grow uncontrollably. ning," Good says. "Success at genetic But in a more modest way, ad and cellular engineering tells us we'll vances in cellular immunology al soon be able to introduce immune ready are providing practical clinical resistance by means of bone marrow benefits. For example, hard-won basic transplants. But first we must learn information about the genetic signa the rules of this game," he notes. D tures recognized by cells of the im mune system has improved the tech nology and widened the applicability Syntheses devised for of bone marrow transplant technol ogy. Bone marrow is the source of the asymmetric compounds immune system cells. And for pa tients with certain kinds of leukemia, Chemists now have a well-stocked in which the bone marrow cells turn tool kit for making almost any desired malignant, successful transplants are optically active compound in high a matter of survival. yields and high optical purity. These Physicians, following close on the methods, almost all of which were heels of scientists describing just what developed in the past five years, will kinds of transplants may succeed, are bear fruit in coming years in the form growing bolder in their development of asymmetric model compounds for of this technology. Recently, a team organic and biochemical mechanism of physicians at Fred Hutchinson studies. Center in Seattle reported success in Total syntheses of natural products treating a leukemia patient with bone also will become increasingly inge marrow cells from an unrelated nious as greater numbers of the new donor. Previously, only transplants methods become available to control between relatives (usually siblings) stereochemistry at each step. Drug had been successful. The donor's manufacture will benefit from this bone marrow cells were, however, revolution in asymmetric synthesis closely matched genetically to those with adaptation of many methods to of the patient. Other teams, particu- commercial production. The food
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Alkaloid catalyzes chiral carbon-carbon bond formation CI3CCH0
Quinidine
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S-(-)-Malicacid
industry and agriculture may use optically active food additives as well as pheromones and insect feeding deterrents for pest control. Chemistry professor Dieter Enders of Justus Liebig University, Giessen, West Germany, pointed out the im portance of having individual enantiomers of asymmetric compounds to a symposium on asymmetric synthe sis in the Division of Organic Chem istry at the Second Chemical Con gress of the North American Conti nent, held last month in Las Vegas. For example, S-asparagine is bitter, whereas the R isomer is sweet. 3Chloro-l,2R-propanediol is toxic, but the S enantiomer is under study as a male antifertility agent. The terato genic effects of phthalidomide come from the S isomer. Enders reminded his audience that
the requirements for asymmetric synthesis are deceptively simple. Using the universal gas constant and a temperature of 25° C, he said, one can calculate that the transition state of a reaction leading to a desired iso mer need be only 3 kcal per mole lower than that leading to the undesired enantiomer. "So, in asymmetric synthesis," Enders says, "this small value, about the same as the rotational barrier of ethane, makes the difference between deep depression and high excitement. Thus, the basic question is: How can one create a free energy difference of 2 to 3 kcal per mole from the com peting transition states of an asym metric synthesis that are very similar in steric and electronic factors?" Enders and other symposium speakers provided answers to this question in terms of asymmetric cat alysts, reagents, and control of reac tion equilibria. Yet a qualification to any answer to Enders' question that also emerged is that there is no unique answer. For any particular asymmetric synthesis, all approaches must be examined. Among those who described suc cessful catalytic asymmetric synthe ses to the symposium was chemistry professor Hans Wynberg of the Uni versity of Groningen, the Nether lands. He and graduate student Emiel Staring reported making the indi vidual enantiomers of malic acid. Wynberg says the technique may become important in the food indus try, where malic acid is used as an acidulant and where there is in-
Reagents made from natural asymmetric compounds aid pheromone synthesis
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24
C&ENSept. 22, 1980
HCI
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creasing interest in using synthetic S-(—)-malic acid, which is the natu rally occurring isomer. The Groningen chemists have found that quinidine catalyzes a re action between chloral and ketene to give quantitative yields of S-(—)7,7,7-trichloro-/3-butyrolactone in 95% enantiomeric excess (97.5% S and 2.5% R isomer). Hydrolysis of the lactone gave S-(-)-malic acid. Use of quinine resulted in a 76% enantio meric excess of the rare, unnatural R-(+)-malic acid. Enantiomeric excess is a measure of enrichment of one enantiomer compared with a racemic mixture. Values greater than 90% show prom ise for syntheses of optically pure compounds. A rule to convert enan tiomeric excess to per cent enriched isomer in a mixture is to divide by two and add 50 to the quotient. In addition to substances used in catalytic amounts, considerable suc cess has come from stoichiometric reagents to induce asymmetry in re actions. Chemistry professor Teruaki Mukaiyama of the University of Tokyo has developed 2S-phenylaminomethylpyrrolidine, which he makes from S-proline, into a versatile reagent to produce optically active aldehydes. He described a synthesis of the Dendroctonus beetle phero mone frontalin in a synthetic se quence based on this reagent. Reaction with methyl glyoxilate produces methyl 2-phenylperhydropyrrolo[l,2-c] imidazole-1-carboxylate, which Mukaiyama treats first with methyl magnesium bromide, then with 4-methyl-4-penten-l-ylmagnesium bromide. Hydrolysis frees optically active 2-hydroxy-2,6-dimethyl-6-heptenal and regenerates the reagent. Reduction of the hydroxylaldehyde, ozonolysis, and cyclization yield S-frontalin of 100% optical purity. Mukaiyama also finds the 2S-(2,6dimethylphenylaminomethyl) re agent useful for asymmetric reduction of ketones to secondary alcohols. He reacts this reagent with lithium alu minum hydride to form a reducing agent with two hydride equivalents. Results range from 11% enantiomeric excess with phenylacetone to 96% with propiophenone. Proline is a good choice for many such reagents. This is because natural S-proline is inexpensive. For reagents of opposite asymmetry, racemic pro line is easily resolved. Also, Enders has developed methods to make re agents based on R-proline from readily available R-glutamic acid. One of Enders' reagents from Sproline is l-amino-2S-methoxymethylpyrrolidine. He used it to make 4S-methyl-3-heptanone, the
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For the creative chemist. 188C
Modaîi
1980
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