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Historical Aspects
Chapter 1
Historical Aspects
I. Some Basic Concepts Recognition of the biological effects of organometallic compounds came virtually with the discovery of these compounds some two centuries ago. Although, to a certain extent, this recognition has developed with the field of organometallic chemistry itself, much of the voluminous research on this subject has been unrelated to the trends in that field (7). Earlier work has been reviewed in two articles (2,5). Table 1.1 presents a chro nology of important discoveries. An organometallic compound (often termed an organometal) contains one or more direct linkages between a carbon atom and a metal atom. The metal is frequently an element such as boron, silicon, phosphorus, arse nic, selenium, or tellurium that is less electronegative than carbon but is not considered a true metal by chemists. The term organometalloid is often used when the organo compounds of these elements are to be differ entiated from organo compounds of true metals. Metal carboxylates, alkoxides, amides, thiolates, and others do not have a metal-carbon bond and are not considered in this volume. Because water is a crucial part of the cellular organization of all terres trial life, organometallic compounds used in biological studies must be sufficiently stable toward water to last long enough for the desired interac tion to occur. This requirement precludes compounds such as the Grignard reagent, alkyllithium derivatives, and various others that react rapidly and exothermically with water. Kinetic rather than thermodynamic considerations are crucial here because, if the reaction with water is sufficiently slow, the organometal can still be used for biological studl
1. Historical Aspects
2
TABLE 1.1 Chronological Summary of Research on Biological Interactions of Organometallic Compounds 1760 1837
1858 1866 1890 1891 1908
1914
1923
1933
1954 1961 1968
Cadet prepares a solution of methylarsenicals and notes the toxic effects. Bunsen begins research on "Cadet's arsenical liquid." He isolates (CH3)4As2, cacodyl, and notes the toxicity of this compound and its derivatives. About this time Gmelin and others begin reporting on "arsenic rooms." Buckton notes the irritating effects of alkyltin compounds on mucous mem branes. First fatality from poisoning by dimethylmercury is reported. Nickel tetracarbonyl is isolated. This leads to the development of the chemistry of metal carbonyls, with concomitant health hazards. Gosio reports that the volatile arsenic species found in "arsenic rooms" exists as an alkylarsenic compound. Ehrlich begins research on the antibiotic activity of aromatic arsenic com pounds, with resulting isolation and application of Salvarsan. This research also lays the foundation for systematic chemotherapy. World War I begins, and various organoarsenicals are used as poison gases. Subsequently, the compound lewisite is prepared, which in turn leads to the development of BAL and related antidotes. Tetraethyllead is developed as a gasoline additive. Deaths of certain people handling this compound lead to the development of safe handling techniques and physiological research. Challenger reports the formation of trimethylarsine by the action of molds on arsenous oxide. His subsequent research leads to the formulation of the concept of biological methylation. Stalinon disaster occurs in France. At this time the first cases of Minamata disease appear. Vitamin Bj2 coenzyme is shown to contain a Co—C bond, making it the first organometallic compound known to be formed as a standard product of biologi cal metabolism. It is reported that methylmercuric compounds can be generated by the action of microorganisms on inorganic mercury compounds.
ies. Some organometals react with water or dilute acid to give metalcarbon bond cleavage: (CH3)4Pb + HX
> (CH3)3PbX + CH4
Because the rate of cleavage might vary substantially in the highly com plex buffering systems characteristic of biological organisms, it may well be important in the circulation and transformation of organometallic com pounds in these organisms, especially since it affects water-lipid parti tion. Still, the basic requirement remains: To be biologically important, an
3
II. Early Chemotherapeutic Uses
organometallic compound must have some degree of stability toward water. Although a few materials (such as the silicones) are biologically inert and are important for this reason, most organometals are toxic. The ma jority of research on organometallic compounds in biological systems has been based on this fact. Toxicity toward Protista and multicellular micro organisms serves as the basis for many medicinal and therapeutic applica tions. Corresponding toxicity toward multicellular invertebrates has given rise to numerous biocidal applications, which in turn have generated nu merous further research efforts. Concern over organometal toxicity to ward vertebrates has led to investigations into the mechanism of action for these compounds and the development of antidotes. This has often enabled investigators to use organometals as probes and reagents for biochemical studies. Organometallic compounds can actually be formed in organisms through biological processes and this formation may well be involved in the biogeochemical cycling of certain metals through the natu ral environment. All of these aspects receive detailed consideration in subsequent chapters. Because the investigations of the roles of organome tallic compounds in biological systems, as in other areas of human activ ity, show a chronological dependence, certain crucial events are taken from Table 1.1 and discussed here in more detail.
II. Early Chemotherapeutic Uses A. Mercurials Compounds of mercury were used for the treatment of disease from the time of Paracelsus (1493-1541) and for many years were particularly im portant in the treatment of syphilis. An early monograph on the organic derivatives of mercury {4) lists 28 proprietary names of mercury-contain ing preparations, 8 of which are organomercurials. Of these, only mercurochrome (1) remains in use today. Mercurochrome and merthiolate (2) serve as mild local antiseptics.
HgCH2CH3
1. Historical Aspects
4
B. Arsenicals and Ehrlich Although scattered reports had appeared earlier, the systematic appli cation of organoarsenicals as antiparasitic agents in medicine began with the work of Paul Ehrlich (5). After establishing the true chemical nature of Atoxyl® as monosodium /?-aminophenylarsonate (6), he began the sys tematic preparation and clinical investigation of hundreds of related or ganoarsenicals. Ehrlich's goal was the "therapia sterilans magna"—the single massive dose of compound that would destroy the infecting para site. He acted on the guiding principle "Corpora non agunt nisifixata" (bodies do not act unless fixed) and placed a wide variety of substituents on both the aromatic ring and the arsenic atom. The enormous number of compounds prepared and investigated in this study provided considerable impetus to develop and expand organoarsenic chemistry (7). Actually, Bunsen had somewhat anticipated Ehrlich's principle when, after examin ing the toxicity of cacodylic acid, he concluded (8): The mode of combination of arsenic in cacodylic acid differs from that in inorganic compounds. Inasmuch as it has ceased to offer a point of attack to affinity, it has simultaneously lost its reactivity in the organism.
The name Atoxyl was coined in the mistaken belief that the compound was not toxic; further investigation showed that it did have appreciable toxicity, although much less than arsenic acid derivatives. Of all the com pounds Ehrlich and his co-workers studied, compound 606 proved to be the most efficacious. Ehrlich named it Salvarsan,® which was the name by which it became known in Europe; in the United States the name used was arsphenamine. For many years this compound was believed to be an arsenic analog of azobenzene; it was drawn as a dimer with As—As double bonds and named 3,3'-diamino-4,4'-dihydroxyarsenobenzene. More recent work showed that the unsubstituted arsenobenzene was ac tually a cyclic hexamer (9) [(C6H6As)6], and it seems probable that Salvar san is also polymeric; it is shown that way in structure 3. HO
HaN
b
"A(
HO
b
-As
NHCH2OSOaNa 4
Salvarsan rapidly became the pharmaceutical of choice for the treat ment of infections by spirochetes or trypanosomes, especially syphilis. Salvarsan itself did not dissolve appreciably in water, and the watersoluble hydrochloride proved to be too toxic for medicinal use. There-
II. Early Chemotherapeutic Uses
5
fore, Salvarsan was dissolved in aqueous hydroxide solution and adminis tered in that form (70). Some time later the water-soluble derivative Neosalvarsan® (no. 914; neoarsphenamine) (4) solved this difficulty. Un fortunately, both Salvarsan and Neosalvarsan oxidized upon contact with air, which meant that they had to be stored under nitrogen in airtight ampules. C. Arsenicals after Ehrlich Research on the organoarsenicals continued after Ehrlich's death in 1915. Mechanistic studies indicated that Salvarsan was oxidized in the body to oxophenarsine hydrochloride (5) (marketed as Mapharsen®). Be cause this compound was stable to air, it gradually replaced Salvarsan in therapy and became the predominant medicinal organoarsenical during the 1930s. The arylantimony compounds stibamine (6) and stibosan (7),
6
HO—( (
HsN+
C
)h-AsO f
5 O
H N
*
Sb
\ 0 /
°s H "
Na+
H H CH3IIC—N-YQV-Sb0 3 H" NH4 Cl
6
7
both derivatives of phenylstibonic acid, received some limited therapeutic usage (77). Organobismuth compounds showed toxicity but never proved to be satisfactory in therapeutic applications (72). Derivatives of antimonyl ion SbO+ and bismuthyl ion BiO+ proved to be effective in the treat ment of various parasitic infections and remain in use for that purpose to this day. Mapharsen and related arsenicals continued to be used in syphilis ther apy during the 1940s but were gradually replaced by penicillin. The pro gress of this change can be traced in the discussions on Mapharsen and penicillin in various syphilology books. A text published in 1941 makes no mention of penicillin (70). This agent did receive attention in a 1944 text (75) and substantial coverage in a 1947 text (14). A text published in 1949 stated (75), "Although penicillin promises to supersede all previous antisyphilitic agents ... arsenoxide Mapharsen will probably continue to have a place in the treatment of some cases of syphilis." A 1951 text on medici-
1. Historical Aspects
6
nal chemistry noted that the fourteenth revision of the U.S. Pharmacopeia had deleted arsphenamine and neoarsphenamine but had retained Mapharsen (11). Finally, in 1969 a book on venereal diseases (16) stated that "there is now no indication for the use of either mercurial or arsenical drugs in the treatment of syphilis." One reason for the discontinuation of these compounds in the treatment of syphilis was the fact that arsenicals frequently caused allergic reactions or damage to the nervous system (13). These ill effects were sufficiently important to warrant a monograph on their prevention (77). The discontinuation of organoarsenicals in syphilis therapy does not mean that they have disappeared altogether. These compounds retain their antiparasitic activity and still receive occasional use in the treatment of animals or as investigatory tools in biochemical laboratory research.
III. Early Work in Organometal Toxicology A. Poison Gases Organoarsenicals were used or prepared for use in World War I. These have been classified according to the effect they produce (18): choking gases (e.g., C6H5AsCl2 and C2H5AsCl2), blistering gases (e.g., CH3AsCl2), and vomiting gases [e.g., (C6H5)2AsCl]. These compounds are liquids at ordinary temperatures and form readily hydrolyzed fogs when sprayed into the air. The most notorious of these gases was lewisite (ClCH=CHAsCl2), which was proposed (but never used) as a blistering gas (79). These gases stimulated the search for antidotes. Various com pounds were proposed, but the most widely used was 2,3-dimercaptopropanol [HSCH2CH(SH)CH2OH], known under the common names of mercaprol or BAL (British anti-lewisite). It acts by bonding to the arsenic atom to form a water-soluble complex, which the body excretes (20,27). BAL remains in gradually diminishing use for the treatment of poisoning by compounds of arsenic, mercury, or other heavy metals. B. Industrial Poisonings Industrial development and expansion have, in a few instances, in volved poisoning by organometallic compounds. The purification of nickel proceeds through the formation and decomposition of the volatile, poisonous gas Ni(CO)4. The hazards of handling this compound were studied and overcome (22), but the physiological effects of metal carbonyls still receive research attention. The discovery that tetraethyllead [(C2H5)4Pb] made a superb gasoline additive generated new industrial
III. Early Work in Organometal Toxicology
7
applications, along with numerous health problems (25). Eighty-eight cases of poisoning by this compound were reported in the United States and Canada (24) between the years 1926 and 1964; scattered cases have occurred since then. The physiological effects of tetraethyllead continue to be investigated, with special reference to environmental pollution. C. Gosio Gas Early in the nineteenth century, cases of arsenic poisoning having no apparent causes were reported in Germany and elsewhere. Such poison ings usually occurred in rooms lined with wallpaper colored with the aid of arsenate salts. Because these rooms were usually damp and poorly ventilated, mold attacked the paper and generated a volatile, malodorous, arsenic-containing compound. Gosio made the first concerted attempt to identify this species and proposed the compound diethylarsine [(C2H5)2AsH] (3). Challenger (25-28) subsequently identified "Gosio gas" as trimethylarsine [(CH3)3As], found that similar transformations oc curred with the oxides of selenium and tellurium, reported that these changes occurred as part of the biological processes within the molds, involving 5-adenosylmethionine as the active intermediate, and coined the term biological methylation to describe the process. A case of poison ing by Gosio gas occurred as recently as 1954 in Italy (29). Biological methylation has subsequently become much more widely known and is discussed extensively in Chapter 9. D. Stalinon Although the toxicity of organotin compounds had been known since the latter part of the nineteenth century, these materials had received little use in medicine. In 1954, 400,000 capsules, intended for treatment of staphylococcal infections and supposedly containing diethyltin diiodide, were distributed in France under the name Stalinon (30). They proved to be an example of "the cure worse than the disease": 102 people died and a like number suffered from various neurological disorders. Subsequent investigation showed that (C2H5)2Snl2 and, even worse, (C2H5)3SnI (present as an impurity) were potent neurotoxic compounds (31-33). As a result of this, organotin compounds are not generally used in medicine but serve as reagents for toxicity studies (Chapter 3) and as pesticides (Chap ters 6 and 8). E. Minamata Disease The most numerous cases of human poisoning by an organometal have involved the ingestion of methylmercuric compounds. Reports of such
8
1. Historical Aspects
cases have come from all parts of the world, but those from Asia have been the most numerous. The methylmercuric compounds were con sumed in two classes of food: marine organisms (fish and shellfish), in the tissues of which these compounds had accumulated from the surrounding waters and sediments; and grain seeds, intended for planting and coated with an antifungal methylmercuric preparation, which were eaten instead. The name Minamata disease was derived from the fact that the first cases of widespread methylmercuric compound poisoning occurred among the people of Minamata Bay, Japan. These cases were reported in 1953, and detailed investigations began in 1956. Investigators isolated the compound CH3HgSCH3 from the tissues of the shellfish Hormomya mutabilis and identified it as the causative agent (34-37). The methylmer curic moiety was subsequently determined to come from the effluent of a factory manufacturing acetaldehyde. In the presence of chloride ion, acetaldehyde and mercuric chloride combined to form CH3HgCl (38). A sec ondary source of methylmercuric compounds became known when two groups reported that bacteria could form them from inorganic mercuric derivatives (39,40). Additional cases of Minamata disease were reported in 1964 in Niigata (41), in 1973 in Ariake, and in Canada, where Indians were poisoned by eating fish from waters contaminated by mercury-containing factory efflu ents (42,43). Numerous cases of methylmercuric poisoning from eating seeds have occurred in Sweden, Iraq, Guatemala, and elsewhere. During the 1960s, the bird population of Sweden became severely depleted for this reason but recovered when such preparations were banned in 1967. Severe outbreaks occurred in Iraq (6000 people admitted to hospitals; 500 deaths) and Guatemala (45 people affected; 20 deaths) (44). One family in the United States suffered similarly when they ate the flesh of hogs that had been fed seeds coated with a methylmercuric preparation (42). Minamata disease and the great suffering it has caused have generated extensive research, which in turn has generated an enormous amount of literature, of which only a portion can be listed here. Both technical (38,45-48) and popular books (42,49,50) have appeared, as have numer ous articles (51-60). Although the problem has receded somewhat from public notice (at least in the United States) since the early 1970s, it re mains quite serious, and there is no assurance that a new outbreak of Minamata disease might not occur somewhere, unexpectedly and tragi cally. The historical development of organometallic chemistry has followed a pattern in which a single new compound is suddenly reported and this compound becomes the focal point for numerous investigations that open up previously unknown areas of chemical reaction. The compounds caco-
References
9
dyl, diethylzinc, the Grignard reagent, nickel tetracarbonyl, Salvarsan, and ferrocene have all followed this pattern, and it seems safe to add methylmercuric chloride to this list. Although not a new compound (it was first reported in 1929) (67), the biological effects are novel, at least in terms of their extent and importance. Methylmercuric chloride has been studied more extensively and intensively in biological system than has any other organometallic compound. The degree of its predominance will become apparent in the succeeding chapters of this volume. Because most of this work is relatively recent, the full contribution of methylmer curic chloride to organometallic chemistry has yet to be realized, although it will probably be merely a matter of time before that is determined.
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
J. S. Thayer, Adv. Organomet. Chem. 13, 1 (1975). H. Gilman, Science (Washington, D.C.) 93, 47 (1941). J. S. Thayer, Organomet. Chem. Rev. 76, 265 (1974). F. C. Whitmore, "Organic Compounds of Mercury," pp. 368-372. Chem. Catalog Co., New York, 1921. F. Himmelweit (ed.), "The Collected Papers of Paul Ehrlich," Vol. 3. Pergamon, Lon don, 1960. P. Ehrlich and A. Bertheim, Ber. Dtsch. Chem. Ges. 40, 3292 (1907); Chem. Abstr. 1, 2715 (1907). G. W. Raiziss and J. L. Gavron, "Organic Arsenical Compounds," pp. 492-513. Chem. Catalog Co., New York, 1923. R. W. Bunsen, Ann. Pharm. 42, 15 (1842). W. R. Cullen, Adv. Organomet. Chem. 4, (1966). J. E. Moore, "The Modern Treatment of Syphilis," 2nd ed., pp. 64-133. Thomas, Baltimore, 1941. A. Burger, "Medicinal Chemistry," Vol. 2, pp. 937-978. Wiley (Interscience), New York, 1951. H. Gilman and H. L. Yale, Chem. Rev. 30, 281 (1942). J. H. Stokes, H. Beerman, and N. R. Ingraham, "Modern Clinical Syphilology," 3rd ed. Saunders, Philadelphia, 1944. S. W. Becker and M. E. Obermayer, "Modern Dermatology and Syphilology," 2nd ed. Lippincott, Philadelphia, 1947. E. W. Thomas, "Syphilis: Its Course and Management," p. 96. MacMillan, New York, 1949. A. King and C. Nicol, "Venereal Disease," 2nd ed., p. 107, Davis, Bristol, 1969. V. Genner, "By-Effects in Salvarsan Therapy and Their Prevention." Lewis & Munksgaard, Copenhagen, 1936. W. H. Summerson, Adv. Chem. Ser. No. 26, 15-22 (1960). K. E. Jackson and M. A. Jackson, Chem. Rev. 16, 430 (1935). R. A. Peters, L. A. Stockton, and R. H. S. Thompson, Nature (London) 156,616 (1945). F. W. Oehme, Clin. Toxicol. 5, 215 (1972).
10 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56.
1. Historical Aspects W. E. Trout, J. Chem. Educ. 15, 77 (1938). S. P. Nickerson, J. Chem. Educ. 31, 560 (1954). S. K. Hall, Environ. Sci. Technol. 6, 31 (1972). F. Challenger, Chem. Ind. {London) 12 July, 657 (1935). F. Challenger, Chem. Rev. 36, 315 (1945). F. Challenger, Q. Rev. Chem. Soc. 9, 255 (1955). F. Challenger, ACS Symp. Ser. No. 82, 1-22 (1978). Anon., Time 23 July, 11 (1956). H. P., Br. Med. J. 1, 515 (1958). T. Alajouanine, L. Derobert, and S. Thieffrey, Rev. Neurol. 98, 85 (1958). P. Cossa, J. Radermecker et al., Rev. Neurol. 98, 94 (1958). J. E. Cruner, Rev. Neurol. 98, 104 (1958). K. Irukayama, T. Kondo, P. Kai, and M. Fujiki, Kumamoto Med. J. 14, 157 (1961); Chem. Abstr. 57, 10378c (1962). K. Irukayama, M. Fujiki, P. Kai, and T. Kondo, Kumamoto Med. J. 15,1 (1962); Chem. Abstr. 58, 10560g (1963). M. Uchida, K. Hirakawa, and T. Inoue, Kumamoto Med. J. 14, 171 (1961); Chem. Abstr. 57, 10378c (1962). M. Uchida, K. Hirakawa, and T. Inoue, Kumamoto Med. J. 14, 181 (1961); Chem. Abstr. 57, 10378d (1962). T. Tsubaki and K. Irukayama (eds.), "Minamata Disease: Methylmercury Poisoning in Minamata and Niigata, Japan," p. 317. Kodansha, Tokyo, 1977. J. M. Wood, F. S. Kennedy, and C. G. Rosen, Nature (London) 220, 173 (1968). S. Jensen and A. Jernelov, Nature (London) 223, 753 (1969). Y. Takizawa, T. Kosaka, R. Sugai, I. Sasagawa, C. Sekiguchi, and K. Minagawa, Acta Med. Biol. 19, 193 (1972); Biol. Abstr. 55, 28899 (1973). P. A. D'ltri and F. M. D'ltri, "Mercury Contamination: A Human Tragedy." Wiley (Interscience), New York, 1977. B. Wheatley, A. Barbeau, T. W. Clarkson, and L. W. Lapham, Can. J. Neurol. Sci. 6, 417 (1979); Biol. Abstr. 70, 6453 (1980). F. Bakir, S. F. Damluji, L. Amin-Zaki, M. Murtadha, A. Khalidi, N. Y. Al-Rawi, S. Tikriti, H. I. Dhahir, T. W. Clarkson, J. C. Smith, and R. A. Doherty, Science (Wash ington, D.C.) 181, 230 (1973). P. M. D'ltri, "The Environmental Mercury Problem." CRC Press, Cleveland, 1971. L. T. Friberg and J. J. Vostal, "Mercury in the Environment." CRC Press, Cleveland, 1972. R. Hartung and B. D. Dinman (eds.), "Environmental Mercury Contamination." Ann Arbor Science, Ann Arbor, 1972. T. Tsubaki and K. Irukayama (eds.), "Minamata Disease: Methylmercury Poisoning in Minamata and Niigata, Japan." Kodansha, Tokyo, 1977. K. Montague and P. Montague, "Mercury." Sierra Club, San Francisco, 1971. W. E. Smith and A. E. Smith, "Minamata." Holt, Rinehart & Winston, New York, 1975. P. Montague and K. Montague, Sat. Rev. 6 Feb., 50 (1971). A. L. Hammond, Science (Washington, D.C.) 171, 788 (1971). Anon., Chem. Eng. News 5 July, 22 (1971). J. M. Wood, Environment 14, 33 (1972). J. J. Putman, Natl. Geog. October, 507 (1972). A. Katz, CRC Crit. Rev. Environ. Control 2, 517 (1972); Chem. Abstr. 78, 106641k (1973).
References
11
57. A. Kojima and M. Fujita, Toxicology 1, 43 (1973); Chem. Abstr. 79, 27985t (1973). 58. T. W. Clarkson, M. R. Greenwood, L. Amin-Zaki, and M. A. Majeed, Br. Med. J. 1, 613 (1978). 59. L. Amin-Zaki, S. Elhassani, M. A. Majeed, T. W. Clarkson, R. A. Doherty, and M. R. Greenwood, J. Pediatr. (St. Louis) 85, 81 (1974); Biol. Abstr. 59, 34720 (1975). 60. L. Amin-Zaki, S. Elhassani, M. A. Majeed, T. W. Clarkson, R. A. Doherty, M. R. Greenwood, and T. Giovanoli-Jakubczak, Am. J. Dis. Child 130, 1070 (1976); Biol. Abstr. 63, 29988 (1977). 61. K. H. Slotta and K. R. Jacobi, J. Prakt. Chem. 120, 249 (1929).
Historical Aspects
I. Some Basic Concepts Recognition of the biological effects of organometallic compounds came virtually with the discovery of these compounds some two centuries ago. Although, to a certain extent, this recognition has developed with the field of organometallic chemistry itself, much of the voluminous research on this subject has been unrelated to the trends in that field (7). Earlier work has been reviewed in two articles (2,5). Table 1.1 presents a chro nology of important discoveries. An organometallic compound (often termed an organometal) contains one or more direct linkages between a carbon atom and a metal atom. The metal is frequently an element such as boron, silicon, phosphorus, arse nic, selenium, or tellurium that is less electronegative than carbon but is not considered a true metal by chemists. The term organometalloid is often used when the organo compounds of these elements are to be differ entiated from organo compounds of true metals. Metal carboxylates, alkoxides, amides, thiolates, and others do not have a metal-carbon bond and are not considered in this volume. Because water is a crucial part of the cellular organization of all terres trial life, organometallic compounds used in biological studies must be sufficiently stable toward water to last long enough for the desired interac tion to occur. This requirement precludes compounds such as the Grignard reagent, alkyllithium derivatives, and various others that react rapidly and exothermically with water. Kinetic rather than thermodynamic considerations are crucial here because, if the reaction with water is sufficiently slow, the organometal can still be used for biological studl
1. Historical Aspects
2
TABLE 1.1 Chronological Summary of Research on Biological Interactions of Organometallic Compounds 1760 1837
1858 1866 1890 1891 1908
1914
1923
1933
1954 1961 1968
Cadet prepares a solution of methylarsenicals and notes the toxic effects. Bunsen begins research on "Cadet's arsenical liquid." He isolates (CH3)4As2, cacodyl, and notes the toxicity of this compound and its derivatives. About this time Gmelin and others begin reporting on "arsenic rooms." Buckton notes the irritating effects of alkyltin compounds on mucous mem branes. First fatality from poisoning by dimethylmercury is reported. Nickel tetracarbonyl is isolated. This leads to the development of the chemistry of metal carbonyls, with concomitant health hazards. Gosio reports that the volatile arsenic species found in "arsenic rooms" exists as an alkylarsenic compound. Ehrlich begins research on the antibiotic activity of aromatic arsenic com pounds, with resulting isolation and application of Salvarsan. This research also lays the foundation for systematic chemotherapy. World War I begins, and various organoarsenicals are used as poison gases. Subsequently, the compound lewisite is prepared, which in turn leads to the development of BAL and related antidotes. Tetraethyllead is developed as a gasoline additive. Deaths of certain people handling this compound lead to the development of safe handling techniques and physiological research. Challenger reports the formation of trimethylarsine by the action of molds on arsenous oxide. His subsequent research leads to the formulation of the concept of biological methylation. Stalinon disaster occurs in France. At this time the first cases of Minamata disease appear. Vitamin Bj2 coenzyme is shown to contain a Co—C bond, making it the first organometallic compound known to be formed as a standard product of biologi cal metabolism. It is reported that methylmercuric compounds can be generated by the action of microorganisms on inorganic mercury compounds.
ies. Some organometals react with water or dilute acid to give metalcarbon bond cleavage: (CH3)4Pb + HX
> (CH3)3PbX + CH4
Because the rate of cleavage might vary substantially in the highly com plex buffering systems characteristic of biological organisms, it may well be important in the circulation and transformation of organometallic com pounds in these organisms, especially since it affects water-lipid parti tion. Still, the basic requirement remains: To be biologically important, an
3
II. Early Chemotherapeutic Uses
organometallic compound must have some degree of stability toward water. Although a few materials (such as the silicones) are biologically inert and are important for this reason, most organometals are toxic. The ma jority of research on organometallic compounds in biological systems has been based on this fact. Toxicity toward Protista and multicellular micro organisms serves as the basis for many medicinal and therapeutic applica tions. Corresponding toxicity toward multicellular invertebrates has given rise to numerous biocidal applications, which in turn have generated nu merous further research efforts. Concern over organometal toxicity to ward vertebrates has led to investigations into the mechanism of action for these compounds and the development of antidotes. This has often enabled investigators to use organometals as probes and reagents for biochemical studies. Organometallic compounds can actually be formed in organisms through biological processes and this formation may well be involved in the biogeochemical cycling of certain metals through the natu ral environment. All of these aspects receive detailed consideration in subsequent chapters. Because the investigations of the roles of organome tallic compounds in biological systems, as in other areas of human activ ity, show a chronological dependence, certain crucial events are taken from Table 1.1 and discussed here in more detail.
II. Early Chemotherapeutic Uses A. Mercurials Compounds of mercury were used for the treatment of disease from the time of Paracelsus (1493-1541) and for many years were particularly im portant in the treatment of syphilis. An early monograph on the organic derivatives of mercury {4) lists 28 proprietary names of mercury-contain ing preparations, 8 of which are organomercurials. Of these, only mercurochrome (1) remains in use today. Mercurochrome and merthiolate (2) serve as mild local antiseptics.
HgCH2CH3
1. Historical Aspects
4
B. Arsenicals and Ehrlich Although scattered reports had appeared earlier, the systematic appli cation of organoarsenicals as antiparasitic agents in medicine began with the work of Paul Ehrlich (5). After establishing the true chemical nature of Atoxyl® as monosodium /?-aminophenylarsonate (6), he began the sys tematic preparation and clinical investigation of hundreds of related or ganoarsenicals. Ehrlich's goal was the "therapia sterilans magna"—the single massive dose of compound that would destroy the infecting para site. He acted on the guiding principle "Corpora non agunt nisifixata" (bodies do not act unless fixed) and placed a wide variety of substituents on both the aromatic ring and the arsenic atom. The enormous number of compounds prepared and investigated in this study provided considerable impetus to develop and expand organoarsenic chemistry (7). Actually, Bunsen had somewhat anticipated Ehrlich's principle when, after examin ing the toxicity of cacodylic acid, he concluded (8): The mode of combination of arsenic in cacodylic acid differs from that in inorganic compounds. Inasmuch as it has ceased to offer a point of attack to affinity, it has simultaneously lost its reactivity in the organism.
The name Atoxyl was coined in the mistaken belief that the compound was not toxic; further investigation showed that it did have appreciable toxicity, although much less than arsenic acid derivatives. Of all the com pounds Ehrlich and his co-workers studied, compound 606 proved to be the most efficacious. Ehrlich named it Salvarsan,® which was the name by which it became known in Europe; in the United States the name used was arsphenamine. For many years this compound was believed to be an arsenic analog of azobenzene; it was drawn as a dimer with As—As double bonds and named 3,3'-diamino-4,4'-dihydroxyarsenobenzene. More recent work showed that the unsubstituted arsenobenzene was ac tually a cyclic hexamer (9) [(C6H6As)6], and it seems probable that Salvar san is also polymeric; it is shown that way in structure 3. HO
HaN
b
"A(
HO
b
-As
NHCH2OSOaNa 4
Salvarsan rapidly became the pharmaceutical of choice for the treat ment of infections by spirochetes or trypanosomes, especially syphilis. Salvarsan itself did not dissolve appreciably in water, and the watersoluble hydrochloride proved to be too toxic for medicinal use. There-
II. Early Chemotherapeutic Uses
5
fore, Salvarsan was dissolved in aqueous hydroxide solution and adminis tered in that form (70). Some time later the water-soluble derivative Neosalvarsan® (no. 914; neoarsphenamine) (4) solved this difficulty. Un fortunately, both Salvarsan and Neosalvarsan oxidized upon contact with air, which meant that they had to be stored under nitrogen in airtight ampules. C. Arsenicals after Ehrlich Research on the organoarsenicals continued after Ehrlich's death in 1915. Mechanistic studies indicated that Salvarsan was oxidized in the body to oxophenarsine hydrochloride (5) (marketed as Mapharsen®). Be cause this compound was stable to air, it gradually replaced Salvarsan in therapy and became the predominant medicinal organoarsenical during the 1930s. The arylantimony compounds stibamine (6) and stibosan (7),
6
HO—( (
HsN+
C
)h-AsO f
5 O
H N
*
Sb
\ 0 /
°s H "
Na+
H H CH3IIC—N-YQV-Sb0 3 H" NH4 Cl
6
7
both derivatives of phenylstibonic acid, received some limited therapeutic usage (77). Organobismuth compounds showed toxicity but never proved to be satisfactory in therapeutic applications (72). Derivatives of antimonyl ion SbO+ and bismuthyl ion BiO+ proved to be effective in the treat ment of various parasitic infections and remain in use for that purpose to this day. Mapharsen and related arsenicals continued to be used in syphilis ther apy during the 1940s but were gradually replaced by penicillin. The pro gress of this change can be traced in the discussions on Mapharsen and penicillin in various syphilology books. A text published in 1941 makes no mention of penicillin (70). This agent did receive attention in a 1944 text (75) and substantial coverage in a 1947 text (14). A text published in 1949 stated (75), "Although penicillin promises to supersede all previous antisyphilitic agents ... arsenoxide Mapharsen will probably continue to have a place in the treatment of some cases of syphilis." A 1951 text on medici-
1. Historical Aspects
6
nal chemistry noted that the fourteenth revision of the U.S. Pharmacopeia had deleted arsphenamine and neoarsphenamine but had retained Mapharsen (11). Finally, in 1969 a book on venereal diseases (16) stated that "there is now no indication for the use of either mercurial or arsenical drugs in the treatment of syphilis." One reason for the discontinuation of these compounds in the treatment of syphilis was the fact that arsenicals frequently caused allergic reactions or damage to the nervous system (13). These ill effects were sufficiently important to warrant a monograph on their prevention (77). The discontinuation of organoarsenicals in syphilis therapy does not mean that they have disappeared altogether. These compounds retain their antiparasitic activity and still receive occasional use in the treatment of animals or as investigatory tools in biochemical laboratory research.
III. Early Work in Organometal Toxicology A. Poison Gases Organoarsenicals were used or prepared for use in World War I. These have been classified according to the effect they produce (18): choking gases (e.g., C6H5AsCl2 and C2H5AsCl2), blistering gases (e.g., CH3AsCl2), and vomiting gases [e.g., (C6H5)2AsCl]. These compounds are liquids at ordinary temperatures and form readily hydrolyzed fogs when sprayed into the air. The most notorious of these gases was lewisite (ClCH=CHAsCl2), which was proposed (but never used) as a blistering gas (79). These gases stimulated the search for antidotes. Various com pounds were proposed, but the most widely used was 2,3-dimercaptopropanol [HSCH2CH(SH)CH2OH], known under the common names of mercaprol or BAL (British anti-lewisite). It acts by bonding to the arsenic atom to form a water-soluble complex, which the body excretes (20,27). BAL remains in gradually diminishing use for the treatment of poisoning by compounds of arsenic, mercury, or other heavy metals. B. Industrial Poisonings Industrial development and expansion have, in a few instances, in volved poisoning by organometallic compounds. The purification of nickel proceeds through the formation and decomposition of the volatile, poisonous gas Ni(CO)4. The hazards of handling this compound were studied and overcome (22), but the physiological effects of metal carbonyls still receive research attention. The discovery that tetraethyllead [(C2H5)4Pb] made a superb gasoline additive generated new industrial
III. Early Work in Organometal Toxicology
7
applications, along with numerous health problems (25). Eighty-eight cases of poisoning by this compound were reported in the United States and Canada (24) between the years 1926 and 1964; scattered cases have occurred since then. The physiological effects of tetraethyllead continue to be investigated, with special reference to environmental pollution. C. Gosio Gas Early in the nineteenth century, cases of arsenic poisoning having no apparent causes were reported in Germany and elsewhere. Such poison ings usually occurred in rooms lined with wallpaper colored with the aid of arsenate salts. Because these rooms were usually damp and poorly ventilated, mold attacked the paper and generated a volatile, malodorous, arsenic-containing compound. Gosio made the first concerted attempt to identify this species and proposed the compound diethylarsine [(C2H5)2AsH] (3). Challenger (25-28) subsequently identified "Gosio gas" as trimethylarsine [(CH3)3As], found that similar transformations oc curred with the oxides of selenium and tellurium, reported that these changes occurred as part of the biological processes within the molds, involving 5-adenosylmethionine as the active intermediate, and coined the term biological methylation to describe the process. A case of poison ing by Gosio gas occurred as recently as 1954 in Italy (29). Biological methylation has subsequently become much more widely known and is discussed extensively in Chapter 9. D. Stalinon Although the toxicity of organotin compounds had been known since the latter part of the nineteenth century, these materials had received little use in medicine. In 1954, 400,000 capsules, intended for treatment of staphylococcal infections and supposedly containing diethyltin diiodide, were distributed in France under the name Stalinon (30). They proved to be an example of "the cure worse than the disease": 102 people died and a like number suffered from various neurological disorders. Subsequent investigation showed that (C2H5)2Snl2 and, even worse, (C2H5)3SnI (present as an impurity) were potent neurotoxic compounds (31-33). As a result of this, organotin compounds are not generally used in medicine but serve as reagents for toxicity studies (Chapter 3) and as pesticides (Chap ters 6 and 8). E. Minamata Disease The most numerous cases of human poisoning by an organometal have involved the ingestion of methylmercuric compounds. Reports of such
8
1. Historical Aspects
cases have come from all parts of the world, but those from Asia have been the most numerous. The methylmercuric compounds were con sumed in two classes of food: marine organisms (fish and shellfish), in the tissues of which these compounds had accumulated from the surrounding waters and sediments; and grain seeds, intended for planting and coated with an antifungal methylmercuric preparation, which were eaten instead. The name Minamata disease was derived from the fact that the first cases of widespread methylmercuric compound poisoning occurred among the people of Minamata Bay, Japan. These cases were reported in 1953, and detailed investigations began in 1956. Investigators isolated the compound CH3HgSCH3 from the tissues of the shellfish Hormomya mutabilis and identified it as the causative agent (34-37). The methylmer curic moiety was subsequently determined to come from the effluent of a factory manufacturing acetaldehyde. In the presence of chloride ion, acetaldehyde and mercuric chloride combined to form CH3HgCl (38). A sec ondary source of methylmercuric compounds became known when two groups reported that bacteria could form them from inorganic mercuric derivatives (39,40). Additional cases of Minamata disease were reported in 1964 in Niigata (41), in 1973 in Ariake, and in Canada, where Indians were poisoned by eating fish from waters contaminated by mercury-containing factory efflu ents (42,43). Numerous cases of methylmercuric poisoning from eating seeds have occurred in Sweden, Iraq, Guatemala, and elsewhere. During the 1960s, the bird population of Sweden became severely depleted for this reason but recovered when such preparations were banned in 1967. Severe outbreaks occurred in Iraq (6000 people admitted to hospitals; 500 deaths) and Guatemala (45 people affected; 20 deaths) (44). One family in the United States suffered similarly when they ate the flesh of hogs that had been fed seeds coated with a methylmercuric preparation (42). Minamata disease and the great suffering it has caused have generated extensive research, which in turn has generated an enormous amount of literature, of which only a portion can be listed here. Both technical (38,45-48) and popular books (42,49,50) have appeared, as have numer ous articles (51-60). Although the problem has receded somewhat from public notice (at least in the United States) since the early 1970s, it re mains quite serious, and there is no assurance that a new outbreak of Minamata disease might not occur somewhere, unexpectedly and tragi cally. The historical development of organometallic chemistry has followed a pattern in which a single new compound is suddenly reported and this compound becomes the focal point for numerous investigations that open up previously unknown areas of chemical reaction. The compounds caco-
References
9
dyl, diethylzinc, the Grignard reagent, nickel tetracarbonyl, Salvarsan, and ferrocene have all followed this pattern, and it seems safe to add methylmercuric chloride to this list. Although not a new compound (it was first reported in 1929) (67), the biological effects are novel, at least in terms of their extent and importance. Methylmercuric chloride has been studied more extensively and intensively in biological system than has any other organometallic compound. The degree of its predominance will become apparent in the succeeding chapters of this volume. Because most of this work is relatively recent, the full contribution of methylmer curic chloride to organometallic chemistry has yet to be realized, although it will probably be merely a matter of time before that is determined.
References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.
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57. A. Kojima and M. Fujita, Toxicology 1, 43 (1973); Chem. Abstr. 79, 27985t (1973). 58. T. W. Clarkson, M. R. Greenwood, L. Amin-Zaki, and M. A. Majeed, Br. Med. J. 1, 613 (1978). 59. L. Amin-Zaki, S. Elhassani, M. A. Majeed, T. W. Clarkson, R. A. Doherty, and M. R. Greenwood, J. Pediatr. (St. Louis) 85, 81 (1974); Biol. Abstr. 59, 34720 (1975). 60. L. Amin-Zaki, S. Elhassani, M. A. Majeed, T. W. Clarkson, R. A. Doherty, M. R. Greenwood, and T. Giovanoli-Jakubczak, Am. J. Dis. Child 130, 1070 (1976); Biol. Abstr. 63, 29988 (1977). 61. K. H. Slotta and K. R. Jacobi, J. Prakt. Chem. 120, 249 (1929).