SYNTHETIC MI~DICINES* VERNON
HARRY, UNIVERSITY OP HAWAII, HONOLULU, T. H. Introduction
Before entering upon a discussion of prescribed length, i t is well to state the exact scope to be covered. My purpose is to discuss chemistry as related to the production and the use of synthetic compounds in medicine. Such medicaments may be duplicates of, or improvements upon, natural products, or wholly the results of human ingenuity. Chemo-medico-synthesis is the ultimate result of centuries of human effort against the ravages of disease. Among the primitive peoples, man began to seek the alleviation of his ills by applying to them herbs and other crude natural products plus much superstition. This practice became monopolized by magicians and priests, who, having no scientific principles to guide them, administered almost every imaginable substance as a medicine, frequently with fatal results. But now and then, among countless failures, these hit-or-miss practitioners of the healing art scored a success, discovering accidentally some natural substance possessing real curative properties and valuable physiological action. Thus came the discovery that an extract of the hark of the cinchon tree of Peru would cure malaria. Then during the Middle Ages, Paracelsus (1493-1541) turned chemistry to the interests of medicine by the introduction of various inorganic remedies. Henceforth, chemistry's relation to medicine was established, a bond that was firmly cemented by Wohler's epoch-making discovery of the first synthetic formation of an organic compound, urea, in 1828-and by the memorable labor of Pasteur. The period for 1828 to 1860 principally marked the theoretical development of synthesis by Wohler, Franklaud, Kekul6, Pasteur, Couper, and many other great savants. With the evolvement of the present system, the structural theory, by Crum Brown and Frankland in 1865-1866, added impetus was given to synthesis. In fact, since then hundreds of thousands of definite compounds, organic and inorganic, have been prepared and cataloged. Now the chemist has possession of a weapon by which he is able to attack nature in her most formidable strongholds, wrest her secrets from her, and utilize them for the benefit of ~nankind. The entirely empirical discovery of mauve by Sir William Perkins in 1856, the synthesis of the first coal-tar medicine, salicylic add, hy Kolbe in 1874, of indigo by Adolf von Baeyer in 1881, and of the valuable alkaloids are a few of the early triumphs. It is worthwhile now to glance a t the relation of synthetic chemistry to medicine. The pathology of a disease, whether germinal or physiological, is carefully studied; comparison between i t and similar ailments is 'First prize-winning college essay, 1929-30. This is one of the five specific titles prescribed under the general topic, "The Relation of Chemistry to Health and Disease." 1550
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made, if necessary; and the curative effects of various medicaments are carefully noted. Then the synthesist, in a well-equipped laboratory and with the aid of the accumulated data, commences to modify, tear down, and even create new molecules until he obtains the ultimum curative. His encroachments on the fields of anesthesia, antiseptics, endocrinology, nutrition, and specifics have been in some cases very fruitful, in others, promising, but of such promise that the medical man of the future is given the assurance that he will ultimately have under his absolute control all diseases known today-and this largely through synthetic chemistry. Anesthetics: General and Local The present high state of surgery could never have been developed by the surgeon with all his aseptic technic if chemistry had not intervened with pain-alleviating substances, anesthetics, hoth general and local in their effects. Formerly the patients suffered tortures, for surgery was extremely barbarous. Now they rest unconscious of the scalpel and the saw. After the discovery of oxygen in 1771, a keen interest arose in the gases. Thus, in 1800, Sir Humphry Davy discovered the fact that nitrous oxide was capable of destroying physical pain. Today, in admixture with oxygen, it is used for anesthesia in dentistry and surgery. In 1846, diethyl ether was noted to possess anesthetic properties. Since then it has become the most important general anesthetic. Its success stimulated a search for newer and better anesthetics. In 1848, followed Dr. James Y. Simpson's discovery of chloroform with its several distinct advantages over nitrous oxide and diethyl ether. A. B. Luckhart and Carter of the University of Chicago discovered, in 1923, the anesthetic properties of ethylene, the nearest approach to an ideal anesthetic--one that can he easily administered, can produce profound coma, and from which the patient can rapidly recover without any ill after-effects. The chemical composition and the synthesis of the above-mentioned compounds are seen in the following equations representing their formation: Nitrous oxide, NpO Gentle heating of NH4NOs = 2H10 N%O (2) Diethyl ether, (CzH5).0 At 120°C., in the presence of AL(SO&, a catalyst, the reaction takes place in two stem. (a) GH~OH HZSO,= (GH~)HSO, HZO (b) CzHaOH (C9Hs)HS04= Has01 (GHs)sO (3) Chloroform (trichloromethane), CHCls KOH = HCOOK CHCls CCl&HO (4) Ethvlene, ClHd c2Hs.~son heated alone, or with concentrated H~SOI,yields CxHd, CzHr.HS04= HpSOl CZH, (1)
+
+ +
++
+
+
+
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Local anesthetics having deep penetrability, but lacking irritating, poisonous properties, are another goal. The molecule of a given drug is scrutinized to reveal what particular group of atoms within it is responsible for the desired physiological effect. This is done by working out the molecule's structural formula and testing its different parts. Then follows the work of synthesizing new compounds having molecules built on architectural plans containing only the desired qualities. The best example of this labor is perhaps that done on the cocaine molecule. Researrh worked out its structural formula to be
Subsequent study determined that only the portion of the molecule that is marked with a star and set off from the rest by a dotted line is responsible for the capacity of cocaine for deadening pain. The remaining part proved to be dangerous. The result was synthetic alkaloids, quite unknown in nature, with molecules cut to specifications. Examples are betaeucaine and novocaine, better than their prototype, hut as yet not ideal. Antiseptics In the 17th century, Anthony von Leeuwenhoeck,' discovered bacteria and protozoa, hut little importance wasattached to these discoveries. In the 19th century, Pasteur, while studying fermentation, rediscovered bacteria. Now, however, these minute organisms attracted the attention of scientists. Succeeding research proved that diseases were caused by various tiny organisms. The important question now was how to overcome these microbes. Thus we find that while Pasteur was developing vaccination other men were working on the value of chemicals as antiseptics and disinfectants. Dr. Joseph Lister, using carbolic acid solutions, introduced antiseptic surgery in 1867. Previously, there were no effective means of combating infections characteristic of surgical operations. In fact, so had were the conditions that to open a person's body cavity was practically the same as signing his death warrant. Since then most of the modem successful antiseptics have been discovered and perfected in the chemical lahoratories. A few that are used are: formaldehyde, phenol derivatives, iodine, Dakin's solution, and hydrogen peroxide. Several synthetic See THISJOURNAL, 7, 1671-3 (July, 1930)
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coal-tar dyes such as neutral acriflavine, ravinol, gentian violet, and hexylresorcinol are coming to the fore as antiseptics. Endocrinology Another important and promising field of chemotherapy is that of the ductless glands, so-called, because, having no special channels or ducts, they secrete directly into the blood their potent incretions, which are thereby carried throughout the body. These endocrinous glands, numerous and of varying importance, regulate growth and metabolism, sexual development and functional activity, and the cardio-vascular, involuntary muscular, and nervous systems, besides having other effects of vital importance in body chemistry. Therefore, their proper functioning is indispensable to the welfare of the body. For this reason, chemotherapy is carefully studying their chemistry and the isolation, identification, and synthesis of their principles. The greatest advances in endocrinology have been made in the investigation of the activity of the most important glands, namely, the pancreas, thyroid, adrenals, and pituitary. In 1922, F. G. Banting and C. H. Best of Toronto isolated insulin, the active principle of the ductless pancreas. Later Abel, having obtained insulin in crystalline form, determined, with the assistance of Jensen and 3H20. Geiling, the empirical formula of the crystals to he CasH6s014NnS. Its synthesis is now awaited. Insulin, essential for carbohydrate metabolism, is extremely useful in controlling symptoms of diabetes mellitus, for it enables the diabetic to metabolize sufficient sugar for the needs of his body. The hormones of the thyroid and of the medullary portion of the adrenals have been isolated, identified, and both thyroxin, C,IHL~O~NIS, and adrenalin, CsHIJN03,have been Synthesized, thus giving medicine powerful, pure remedies. Thyroxin is principally used in treating simple goiter, cretinism, myxedema, abnormal metabolism, and obesity, all resulting from hypothyroidism. A few uses of adrenalin are prolonging anesthesia by constricting the blood vessels, relieving of difficultbreathing in asthma, stimulating and supporting the heart, and counteracting Addison's disease. In the pituitary gland, the anterior lobe (hypophysis) is essential for normal growth, sex development, and the development of some of the other glands, including the thyroid and the adrenals. Robertson obtained tethlin from the corresponding lobe in the ox. Drs. Abel and Rouiller secured pituitrin, another principle, from the posterior lobe (infundibulum) related to the contraction of involuntary muscles and to carhohydrate metabolism. Pituitrin, very useful in obstetrics, but not yet synthesized, has been separated by Dr. Kamm of Detroit into two parts
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designated as alpha and beta, respectively, useful in obstetrics and surgery and bums, besides controlling the water content in the body cells. Nutrition Man wonld undoubtedly be immensely benefited if he could master the synthesis of foods and of the essential nutritional factors such as amino acids, enzymes, and vitamins. Only chemistry, by compassing the synthesis of these organic products, can release him from his dependence upon the plant and animal kingdoms for his sustenance. Progressively the end will be reached; one by one the necessary foodstuffs will he prepared, first in the laboratory, later in the food factory. Emil Fischer's investigations on the sugars has led to the synthesis of numerous simple sugars and to the recent work on carbohydrate metabolism and its pathologic variations found in diabetics. The foundation of modern research on protein metabolism is formed by his work on amino acids. It has been shown that several amino acids found in natural proteins are essential for normal nutrition and health. In the absence of these necessary substances, e. g., cystine and histine, animals become unhealthy, develop definite symptoms, fail to maintain themselves, do not reproduce, and may even die. These disorders may be remedied by adding the deficiencies to the incomplete proteins. For instance, a disease designated as acystinosis is relieved and overcome by administration of cystine, which, by the way, has been chemically identified. A thorough understanding of the action of even one enzyme might throw considerable light on the various physiological actions that contribute to what we call life. Moreover, ihe synthesis of such substances wonld be a boon to the anemic, the dyspeptic, and others. The outstanding work being done on pepsin, the proteolytic enzyme of the gastric juice, although not yet successful, promises future victory for the chemist in this field. During recent years a great deal of attention has been focused on the causes of nutritional disorders, the avitaminoses, known to be due to the absence of vitamins, so-called accessory food factors. Thus far, six vitamins and their relations to the nutrition, functioning, and development of the body are known, namely: Vilnmin
A B C D
E PP
Funrlion
Antiophthalmic Growth-promoting Antineuritic Antiscorbutic Antirachitic Reproductive Antipellagric
Notwithstanding what is known concerning these vital nutritive catalysts, the chemist is still confronted with the problems of isolating, identifying,
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and synthesizing them. The best he has been able to do is to prepare such concentrates as Miller's Bios I and 11, Seidell's crystalline picrate possessing antineuritic properties, Eddy's growth-stimulating bios, C2HllN0a, and irradiated ergosterol, the potent specific for rickets. These advances promise that we may confidently expect the final artificial production of a t least some of the amino acids, enzymes, and vitamins to the undoubted advantages of medicine.
Specifics The chemist's problem in producing specifics is to secure medicaments destructive to particular germs but harmless to the patient. Here he has two alternatives, viz., (1) he may improve natural remedies, or (2) he may modify some promising compound. An example of the former plan is the work being done on chaulmoogra oil, used for leprosy. In the Orient, where this disease is rather prevalent, the only medicine has been the crude, unsavory oil taken in through the mouth. The chemist, after studying and experimenting with this oil, has obtained fatty esters which are being used hypodermically more successfully. At the University of Hawaii the research department is striving to obtain a water-soluble fatty ester. Perhaps since the structural formula of chaulmoogric acid, HC-CH(CH&EOOH I
I
I
is now known, the remarkable work done on cocaine may'be duplicated. Paul Ehrlich was the first to succeed by the second method of procedure. Working on the staining properties of aniline dyes, he became convinced that dyes could be very efficient medicinal weapons. Therefore, with this thought in mind, he set to work preparing a specific for syphilis. After 605 failures, covering two years of skilful chemical synthesis, he discovered arsphenamine, his "606" compound, chemistry's greatest triumph in this field. This advent marked the beginning of other brilliant discoveries, for it demonstrated the chemist's power of transforming one form of matter into another more serviceable to man. Although only two absolute specifics, quinine for malaria, and arsphenamine for syphilis and African sleeping sickness, are known, many near specifics have been prepared. For sleeping sickness "Baeyer 205," "Pasteur 309," and tryparsamide, which is also an important drug for the treatment of paresis, are valuable remedies. Carbon tetrachloride, chenopodium, and thymol are effective anti-hookworm agents. Gentian violet ,
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has a selective action against gram-positive staphylococci, whereas acid fuchin kills Gram-negative bacteria. Ravinol is said to act primarily as an inhibitive for streptococci and staphylococci. Mercurochrome has proved valuable for septicemia. Among other synthetics having special applications are homatropine, used to dilate the pupil of the eye, and theophyllin, one of the best diuretics. Conclusion Thus in a brief survey has been shown the trend of chemistry to provide medicine with synthetic medicaments. Anesthetics, antiseptics, endocrinons principles, specifics, and other synthetic products! Imagine where modern civilization would be without them! Yet only the surface of the possibilities of chemo-medico-synthesis has been scratched. And so great is the progress of this new chemistry that perhaps even those horn today may live to see the preparation of synthetic antitoxins, laboratory substitutes for all endocrinous incretions, and even the conquest of cancer and tuberculosis ! References 1. Abel, J. J., "Chemistry in Relation t o Medicine," THISJOURNAL. 6, 10454~4 (June, 1929). 2. Abstracts and miscellaneous articles in THISTOURNAL for 1928 and 1929. 3. Davis, T. I,., "Boerhaave's Account of Paracelsus and Van Helmont," THIS J o u n ~ a L ,5, 6 7 1 4 1 (June, 1928). 4. Deming. H. G., "General Chemistry," John Wiley & Sons, Inc., New York City, 1924, pp. 236-7, 313, 362, 376-80. 5. Forbes, J. C., "The Purification of Pepsin," THISJOURNAL, 6, 127741 (July Aug., 1929). 6. Garvan, F . P., Acceptance Address, THISJOURNAL, 6, 1072-5 (June, 1929). 7. Institute of Margarine Manufacturers, BuUetin No. 11, "The Economics of Vitamines." 8. Parke,Davis & Co., "Lectures on Biological Products." Ch. VIII. 9. Stieglitz, J., "Chemistry and Recent Progress in Medicine," The Chemical Foundation, Inc., 1928. 10. Thorpe, J. F., "One Hundred Years of Organic Synthesis." THE JOURNAL, 5, 1591-602 (Dec., 1928.)
