Chemotherapeutic agent

In 1546, Girolamo Fracastro of Verona proposed the then remarkable theory that diseases were transmitted by minute particles of living matter with the properties of multiplication and airborne dissemination. He considered that particles with great 

In 1910, Ehrlich made a historic discovery while investigating one of these arsenicals, the antisyphilitic drug arsphenamine. This particular drug, with the laboratory code designation 606, was so effective in laboratory tests that it was announced as a cure for the dreaded disease and was referred to as a magic bullet . Although the marketed form of the chemical, Salvarsan, ultimately proved to be too toxic for human use, arsphenamine was the opening event in the chemotherapeutic revolution for the treatment of human infections. 

One of the most important events in the history of antibiotics is the discovery and production of penicillin. In 1928, while investigating staphylococcus variants at St Mary s Hospital in London, Alexander Fleming observed that when a particular strain of mold, Penicillium notatum (named because the cells were pencil-shaped when viewed under a microscope), contaminated these cultures they underwent lysis. Fleming named the active substance penicillin. Unfortunately, because Fleming was such a poor public speaker, his public presentation of his seminal discovery went unheeded, and it took an additional 12 years before the potential of penicillin was realized. 

Several natural penicillins can be produced, depending on the chemical composition of the fermentation medium used to culture penicillium. Penicillin G (benzylpenicillin) has the greatest antimicrobial activity of these natural penicillins and is the only natural penicillin used clinically. However, penicillin G is not stable it is extremely acid-labile. Only about one-third of an oral dose is absorbed under the most ideal conditions. Therefore, it is generally not given orally but is administered by intramuscular injection. Several newer derivatives of penicillin G have been developed that do have good to excellent oral absorption (e.g., cloxacillin, ampicillin, and amoxicillin). 

As discussed earlier, there are a number of ways by which an antibiotic can selectively interfere with biochemical processes in a microbe. This part of the chapter deals in more detail with the respective mechanisms. These include the cell wall and membrane, nucleic acid and protein synthesis, and intermediary metabolism. 

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The field of organogermanium chemistry is becoming increasingly important. Gertain germanium compounds have a low mammalian toxicity, but a marked activity against certain bacteria, which makes them useful as chemotherapeutic agents. 

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Modem cancer therapy has been primarily dependent upon surgery, radiotherapy, chemotherapy, and hormonal therapy (72) (see Chemotherapeutics,anticancer Hormones Radiopharmaceuticals). Chemotherapeutic agents maybe able to retard the rate of growth, but are unable to eradicate the entire population of neoplastic cells without significant destmction of normal host tissue. This serious side effect limits general use. More recentiy, the immunotherapeutic approach to cancer has involved modification and exploitation of the cellular and molecular mechanisms in host defense, regulation of tissue proliferation, tissue differentiation, and tissue survival. The results have been more than encouraging. 

The conjugation of monoclonal antibodies (MoAbs) to radioisotopes, chemotherapeutic agents, and protein toxins has also been given consideration (65). Large amounts of human MoAbs can be produced by biotechnological means. 

Phenyllithium can be used in Grignard-type reactions involving attachment of phenyl group, eg, in the preparation of analgesics and other chemotherapeutic agents (qv). It also may be used in metal—metal interconversion reactions leading, eg, to phenyl-substituted siUcon and tin organics. 

The most common oxidation states and corresponding electronic configurations of platiaum are +2 which is square planar, and +4 which is octahedral. Compounds in oxidation states between 0 and +6 [t) exist. Platiaum hydrosilation catalysts are used in the manufacture of siHcone polymers. Several platiaum coordination compounds are important chemotherapeutic agents used for the treatment of cancer. 

Conra.d-Limpa.ch-KnorrSynthesis. When a P-keto ester is the carbonyl component of these pathways, two products are possible, and the regiochemistry can be optimized. Aniline reacts with ethyl acetoacetate below 100°C to form 3-anilinocrotonate (14), which is converted to 4-hydroxy-2-methylquinoline [607-67-0] by placing it in a preheated environment at 250°C. If the initial reaction takes place at 160°C, acetoacetanilide (15) forms and can be cyclized with concentrated sulfuric acid to 2-hydroxy-4-methylquinoline [607-66-9] (49). This example of kinetic vs thermodynamic control has been employed in the synthesis of many quinoline derivatives. They are useful as intermediates for the synthesis of chemotherapeutic agents (see Chemotherapeuticsanticancer). 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Because of their limited, activity, small spectmm, and side effects, the older topical antimycotics have generally been surpassed by newer antimycotic chemotherapeutic agents. These newer antimycotics for topical use iaclude the imida2ole derivatives clotrimazole, miconazole, econazole, isoconazole, sulconazole, fenticonazole, oxiconazole, bifonazole, butoconazole, ziaoconazole, tioconazole, and the triazole derivative, terconazole (Table 2) (5—7). The iatroduction of the azole derivatives represents a milestone ia the treatment of mycoses. 

Fig. 7. Structures of hormone chemotherapeutic agents given in Table 6.

Miscellaneous Agents. Those chemotherapeutic agents, which do not fit into any of the classifications discussed, ate Hsted iu Table 7. Mitotane (67), a stmctural isomer of DDT, is used to iaduce chemical adrenalectomies iu patients having adrenal cancer by teduciug host levels of adrenocorticosteroids. 

A.ntibiotic is an organic chemical substance produced by microorganisms that has the capacity in low concentration to selectively destroy or inhibit the growth of other microorganisms without injuring the host cells. It may be adrninistered systemicaHy and be an antimicrobial chemotherapeutic agent. 

Sulfur dioxide, sulfites, and metabisulfites have had extensive use as antimicrobial preservatives in the food industry. In pharmaceuticals they have had a dual role, acting as preservatives and antioxidants. The sulfa dmgs, or sulfonamides, the first effective chemotherapeutic agents to be employed... 

Furan-2-carbaldehyde, 5-methyl-synthesis, 4, 658 Furan-2-carbaldehyde, 5-nitro-as chemotherapeutic agent, 1, 179... 

African sleeping sickness and, 1, 180 as chemotherapeutic agent, 1, i80 veterinary use, 1, 208 Furfuracryluric acid as metabolite of furfural, 1, 245... 

The last decade has brought a considerable increase of the number of papers concerned with 1,3-oxazine derivatives. This is due partly to the fact that these compounds show interesting reactivity. Hence, it was suggested recently that 1,3-oxazine derivatives (including benz-l,3-oxazine derivatives) should be used as chemotherapeutic agents. ... 

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