Immunopharmacological Drugs

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The ability of the body to independently protect itself from certain diseases is called immunity. In a medical sense, immunity is a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity to certain diseases can be both inherent and acquired. Most types of immunity are either acquired during the course of life in response to infection by various microorganisms (actively acquired immunity), or it can be attained by specific, directed production of antibodies in the body in response to previous artificial infection by dead or weakened microorganisms (passively acquired, artificial immunity), which is usually obtained through vaccinations. Immunization, or selective strengthening of the immune response of the body, is one of the ways of fighting infectious diseases through vaccinations, i.e. producing antigens against concrete, specific pathogens. Undoubtedly, inflammation is also an immune response. Drugs described in other chapters, such as antihistamine agents, nonsteroid anti-inflammatory agents, antiserotonin drugs, and many others can also be formally grouped with immunopharmacological agents. However, only the drugs having a direct effect on cells that have immune functions, such as lymphocytes, plasma cells, and subtypes of these cells will be examined in this chapter. It should be noted that the vital functional products of these cells themselves, such as lymphokines, interferons, and interleukins, are very important immunopharmacological drugs. The immune system has an enormous number of antigens that differentiate between ‘own’ and ‘alien’ molecules. It plays a huge role in autoimmune diseases, hypersensitivity reactions in the body to certain irritants, and in transplant rejections. The immune system is vitally important not only for protecting the body from foreign bodies of organic or inorganic origins, but also from our own cells that transform into foreign cells. It also serves to remove sick, dead, or foreign cells, and, in all likelihood, serves as the body’s primary protection against cancer, suppressing many tumor centers and frequently preventing the formation of metastases. Various drugs are capable of affecting specific immune reactions. They can both increase the general resistivity of the body or its nonspecific immunity, as well as suppress the body’s immune reactions. Hence controlling diseases with immunological agents means either generation of the necessary immunity in the body, or suppression of undesirable immune reactions. It is evident that immunopharmacological drugs are of great significance in diseases of the immune system, organ transplants, viral infections, and in particular, in the treatment of AIDS. 419

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31.1

IMMUNOSTIMULANTS

Enhancing the overall resistivity of the body is observed upon treatment with a number of known drugs: immunostimulants (caffeine, phenamine, methyluracil), vitamins (retinol, ascorbic acid, vitamins of group B), nucleic acid derivatives, and also drugs of natural or genetically engineered origin made specifically for this purpose. They include proteins such as lyphokines, in particular, interleukin-2, which is a glycoprotein containing 133 amino acids, and also the so-called colony stimulating factors (CSF) that of macrophages or granulocytes produced by a few cells, including CSF-multi or interleukin-3, granulocytosis stimulating factor (GSF) a nonglycoside protein, macrophage stimulating factor (MSF) a highly glycosylated homodimer protein, and GMSF (a factor that stimulates both granulocytes and macrophages), a monomeric glycoprotein, which stimulates proliferation, differentiation, and functionalization of target cells in various stages of development. For this purpose, drugs called FNT-α and FNT-β have been made, which are factors that cause tumor necrosis. Interferons—a family of glycoproteins processed by macrophages—also are widely used as immunostimulants; (α -interferons), made in macrophages and fibroblasts; (β-interferons), made in lymphocytes; (γ-interferons), which are named for their ability to react with viral RNA and affect protein synthesis. Commercially accessible α-, β-, and γ interferons are currently used in medicine. Practically the only purely synthetic immunostimulant drug that is used is levamisole, which was initially proposed as an anthelminthic agent, and it is currently widely used as such. Levamisole: Levamisole, 2,3,5,6-tetrahydro-6-phenylimidazo[2,1-b]thiazole (31.1.4), is synthesized in various ways. One of them begins with α-bromoacetophenone, the reaction of which with 2-imino-1,3-thiazolidine gives 3-phenacyl-2-imino-1,3-thiazolidine (31.1.1). Reacting this product with acetic anhydride gives 3-phenacyl-2-acetylimino-1,3thiazolidine (31.1.2). The ketone group in the resulting compound is reduced to an alcohol using sodium borohydride, and the resulting hydroxyl group in (31.1.3) is replaced with chlorine using thionyl chloride. Heating the product in acetic anhydride, the imidazole cycle closes, forming the product (31.1.4).

C

CH 2 Br

+

C H N

S

CH 2

N

S

N COCH 3

O

N H

O

N H

O

(CH 3CO) 2O

C

CH 2

CH

CH 2

N

N COCH 3 1. SOCl 2 2. (CH 3CO)2 O S

S

NaBH 4

31.1.2

31.1.1

OH

N

N

S N

31.1.3

31.1.4

A somewhat different approach was realized when using styrene oxide as the initial starting material. Reacting it with 2-imino-1,3-thiazolidine gives 3-(2-phenyl-2-hydroxyethyl)2-imino-1,3-thiazolidine (31.1.5), which is subsequently treated with thionyl chloride and then acetic anhydride to give the desired levamisole (31.1.4).

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Finally, the following scheme of making the product has been proposed using the same styrene oxide. Styrene oxide is reacted with aziridine, forming 2-aziridion-1phenylethanol-1 (31.1.6). Treating this with potassium isothiocyanate or thiourea gives 3(2-phenyl-2-hydroxyethyl)-2-amino-1,3-thiazolidine (31.1.5), and subsequent treatment with thionyl chloride (such as described above) and then with acetic anhydride gives the desired levamisole (31.1.4) [1–12]. O +

CH H N

N H

OH

N H S

CH 2

N

SOCl 2 (CH 3CO) 2 O

S

N

S N

31.1.5

31.1.4

OH

O

CH +

CH 2

N

H N 31.1.6

Levamisole has immunomodulating activity. It is believed that it regulates cellular mechanisms of the immune system, and the mechanism of its action may be associated with activation and proliferative growth of T-lymphocytes, increased numbers of monocytes and activation of macrophages, and also with increased activity and hemotaxis of neutrophylic granulocytes. Levamisole also exhibits anthelmint action. It also increases the body’s overall resistivity and restores altered T-lymphocyte and phagocyte function. It can also fulfill an immunomodulatory function by strengthening the weak reaction of cellular immunity, weakening strong reaction, and having no effect on normal reaction. Levamisole is used for initial and secondary immunodeficient conditions, autoimmune diseases, chronic and reoccurring infections, large intestine adenocarcinoma, helmintosis, and rheumatoid arthritis. Synonyms of this drug are decaris, tetramizole, and others.

31.2

IMMUNODEPRESSANTS

Along with immunostimulants, drugs are needed in medical practice that suppress immunogenesis, antibody production (which is especially important in transplantation of various tissues and organs, during which the body produces antibodies that cause death of transplanted tissue), and also for treating a few autoimmune diseases. Substances of various pharmacological groups exhibit immunodepressive activity: glucocorticoids, cytostatics, and antibiotics (cyclosporine). 31.2.1

Glucocorticoids

Many synthetic glucocorticoid derivatives are widely used as immunodepressants. Glucocorticoids (cortisone, prednisone, methylprednisolone, betamethasone, dexamethasone,

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triamcinolone, and others) are usually used in combination with other immunodepressants, especially in cases accompanied by inflammation. Immunodepressive action of glucocorticoids is connected with a decreased level of lymphocytes, eosinophiles, and basophiles in the blood, suppression of antigen recognition, and with suppression of the phase of lymphocyte proliferation. 31.2.2

Cytotoxic drugs

Presumably, any cytotoxic substance that destroys bone marrow and lymphoid tissue may be used as an immunosuppressant. Among these drugs, the most widely used primarily for autoimmune diseases are vincristine, methotrexate, and cytarabine. However, their use should be considered experimental. Only methotrexate is seriously and sufficiently recognized as an initial drug for treating rheumatoid arthritis. In addition, one of the sulfur analogs of mercaptopurine, azathioprine, has been proposed as a cytotoxic drug, and it turned out to be more effective as an immunosuppressant. Azathioprine: Azathioprine, 6-[(1-methyl-4-nitroimidazol-5-yl)thio]purine (31.2.1), is synthesized by heteroarylation of the sulfhydrile group of 6-mercaptopurine (30.1.2.9) with 5-chloro-1-methyl-4-nitroimidazol in the presence of sodium acetate as a weak base [13]. N H S

S

N

N N

N CH3

O 2N

N

N

CH3COONa

+

N

N

N CH3

O2N

N Cl

H

N

H 31.2.1

As a matter of fact, azathioprine is a prodrug since it turns into mercaptopurine in the body. This is a possibly reason why it is advantageous over mercaptopurine as an immunosuppressant. The mechanism of action of azathioprine as a cytotoxic drug is not different from the mechanism of action of other antimetabolites. Azathioprine is the primary drug used for transplants, especially for kidney transplants. Today, cyclosporine is used instead of azathioprine in many places. However, azathioprine is useful in combination with cyclosporine, and it is even preferred in certain cases. Synonyms of this drug are azumec, imuran, and others. Cyclophosphamide: Synthesis and properties of this drug are described in Chapter 30. O

P N

O

CH 2 CH 2 Cl N

H

CH 2 CH 2 Cl

30.2.1.15

Besides being used as an alkylating agent in cancer chemotherapy, cyclophosphamide is a unique drug when used as an immunosuppressant. First, it is the most powerful of all such drugs. Second, it kills proliferating cells, and evidently alkylates a certain region of

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remaining cells. Finally, its action on T-cells is such that despite its overall suppressive effect, it can, in certain environments, suppress the response of these cells to antigens. Cyclophosphamide is successfully used for bone transplants. In small doses, it is effective for autoimmune disorders. Cyclosporine A: Cyclosporine A, [R-[R*,R*-(E)]]-cyclo-(L-alanyl-D-alanyl-N-methyl-Lleucyl-N-methyl- L -leucyl-N-methyl- L -valyl-3-hydroxy-N,4-dimethyl- L -2-amino-6octenoyl-L-α-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucine) (31.2.2), is extracted from a cultural liquid of products of the vital activity of the mushroom Tolypocladium inflatum [14–17], and which is also proposed to obtain synthetically [18–20]. CH 3

H

CH 3

CH 3 H CH 2 CH CH 3 CH 3 CH 3 HO CH CH 3 CH 2 CH CH 2 CH 3 CH CH 3 N CH C N CH C N CH C N CH C N CH 2 1 O C 10 O CH 311 O CH 3 O H 2 O 3 C O CH CH 2 CH 9 N CH 3 H O 6 H O CH 3 N 8 H O 7 O 5 4 O C CH N C CH N C CH N C CH N C CH CH 3

CH 2 CH 3 CH CH 3 CH CH 3

CH 3 CH 3

CH 3

CH 3

CH 2 CH CH 3

31.2.2

Cyclosporine A is a powerful immunosuppressive drug intended for preventing rejection of kidney, heart, and lung transplants. A new era in the development of immunopharmacology began with the discovery of cyclosporines. Cyclosporines are produced by mycelial mushrooms Tolypocladium inflatum, Tricoderma polysporum, and Cylindrocarpon lucidum, which are found in the ground. Cyclosporine A is the first drug to affect a specific line of protecting cells of the body. Unlike usual cytotoxics, it suppresses T-cells and acts on all cell lines simultaneously. Cyclosporine A significantly eases the ‘reception’ of transplants, and increases the possibility of treating autoimmune system diseases. All cyclosporines (A,B,C, … U,V,W), are oligopeptides containing 11 amino acids closed in a cyclic form. All of these are known amino acids except the first, which sometimes has not been isolated from natural sources. All of them are L-amino acids except for the amino acids in positions 3 and 8. Because of all of the hydrogen bonds, the structure of cyclosporine is quite rigid. Cyclosporines (A,B,C, … U,V,W) only differ in the second amino acid. Cyclosporine A itself and a number of other cyclosporines have been completely synthesized. Many structural analogs have also been synthesized, and a few patterns have been discovered in terms of their structure and activity. It is known that the activity of the drug is determined by the entire cyclic structure, and not by its separate fragments. Likewise, it is also clear, that the structure of amino acids at position 1 is an important factor of

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determining activity. Despite the fact that the molecule is relatively large, cyclosporine easily diffuses through the cellular membrane. It is possible that there are no corresponding ‘recognizing’ receptors for cyclosporine. However, there is a cytosol cyclosporine-binding protein known as cyclophilin, which has a molecular weight of about 15,000. Cyclophilins are observed mainly in T-cells; however, they are found in other tissues, in particular, in the brain and kidneys. Their exact function and purpose are not known. It is suspected that they control RNA during the synthesis of lymphokines. Since the mechanism of action of cyclosporine is still being intensively studied, it must be noted that it is not cytotoxic in the general sense of the word, because it suppresses bone marrow function. Despite the fact that cyclosporine has not been used for a long time, it is the number one drug used for transplants. Cyclosporine is also being studied as a substance for treating a number of autoimmune diseases, including diabetes, multiple sclerosis, myasthenia, rheumatoid arthritis, and psoriasis. It also has had a great effect in treating schistosomiasis, malaria, and filariasis. Synonyms of this drug are sandimmun and neural.

REFERENCES 1. A.M. Rayemaekers, C.C.D. Thienpont, P.J.A. Demoen, U.S. Pat. 3.274.209 (1966). 2. A.H.M. Rayemaekers, F.T.N. Allewijn, J. Vandenberk, P.J.A. Demoen, T.T.T. Van Offenwert, P.A.J. Janssen, J. Med. Chem., 9, 545 (1966). 3. L.D. Spicer, M.W. Bullock, M. Garber, W. Groth, J.J. Hand, D.W. Long, J.L. Sawyer, R.S. Wayne, J. Org. Chem., 33, 1350 (1968). 4. A.H.M. Rayemaekers, L.F.C. Laevens, P.A.J. Janssen, Tetrahedron Lett., 1467 (1967). 5. M.W. Bullock, J.J. Hand, E. Waletzky, J. Med. Chem., 11, 169 (1968). 6. J. Mueller-Roemer, Ger. Pat. 1.076.651 (1966). 7. American Cyanamid Company, Br. Pat. 1.076.109 (1965). 8. M.W. Bullock, U.S. Pat. 3.565.907 (1971). 9. R.A. Dewar, V.E. Maier, M.A. Ingra, U.S. Pat. 3.579.530 (1971). 10. P. Doyle, A.G. Alastair, U.S. Pat. 3.478.047 (1969). 11. A.Ch. Barker, P.F. Southern, U.S. Pat. 4.070.363 (1978). 12. G. Murray, U.S. Pat. 4.107.170 (1978). 13. G.H. Hitchings, G.B. Elion, U.S. Pat. 3.056.785 (1962). 14. E. Harri, A. Ruegger, U.S. Pat. 4.117.118 (1978). 15. W. Meyer, Ger. Pat. 2.455.559 (1974). 16. A. Ruegger, M. Kuhn, H. Lichti, H.R. Loosli, R. Huquenin, Ch. Quiqueres, A. Von Wartburg, Helv. Chim. Acta., 59, 1075 (1976). 17. H. Kobel, R. Traber, Eur. J. Appl. Microbiol. Biotechnol., 14, 237 (1982). 18. R.M. Wenger, Angew. Chem., 97, 88 (1985). 19. R.Wenger, Transplant. Proc., 15(4, Suppl. 1), 2230 (1983). 20. R.Wenger, Eur. Pat. Appl. 34 567 (1981).