Cancer chemotherapy synthesis

Therapy with L-asparaginase is most successful against tumors exhibiting a deficiency in the synthesis of L-asparagine. Most normal cells exhibit a healthy capacity to synthesize this nonessential amino acid and are not damaged by exposure to L-asparaginase (23). This finding demonstrates that biochemical differences between normal and cancer cells can be exploited for successful cancer chemotherapy. 

Dronabinol (tetrahydrocannabinol), the active principle from cannabis and synthetic cannabinoids, nabilone and levonantradol are effective in treating nausea and vomiting in cancer chemotherapy. The mode of action is unclear but appears to involve cannabinoid CBi receptors. Cannabinoids have been shown to reduce acetylcholine release in the cortex and hippocampus, and have been suggested to inhibit medullary activity by a cortical action. Inhibition of prostaglandin synthesis and release of endorphins may also be involved in the antiemetic effect. A review of trials of dronabinol, nabilone or levonantradol concluded that while the cannabinoids were superior to placebo or dopamine receptor antagonists in controlling emesis... 

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34—2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenofic acid (reaction 14). 

The two alkaloids vinblastine and vincristine found in Catharanthus roseus have been recent targets of total synthesis because of their potency in cancer chemotherapy. The reduced tree diagram for the Fukuyama plan to vincristine is shown in Figure 4.66. There are three points of convergence, four branches leading to the target product and four tiers of reaction yields. 

So, the 20th century actually led to an almost total disappearance of C. sativa for medicinal purposes. The only source for THC, which became the focus of scientific research, was fhe rafher fedious exfracfion and purification from confiscated hashish or marihuana. In 1972 the first commercially viable total synthesis of A9-THC was established and it became the first cannabinoid available as a modern medicine in the form of soft gel capsules (the active ingredient being called dronabinol from tetrahydrocannabinol) under the trade name Marinol for the prevention of nausea and vomiting during cancer chemotherapy. 

A total synthesis of (+ )-vinblastine widely used in cancer chemotherapy, has been reported. It includes the synthesis of (-)-vindoline. 1,3-Dipolar cycloaddition of a nitrile oxide has played an important role in the preparation of the indoloazacycloundecane moiety, whose coupling with (-)-vindoline occurs with the desired stereochemistry, leading to an intermediate readily transformed to the target (+ )-vinblastine (492). 

P. K. Chakravarty, P. L. Carl, M. J. Weber, J. A. Katzenellenbogen, Plasmin-Activat-ed Prodrugs for Cancer Chemotherapy. 1. Synthesis and Biological Activity of Pepti-dylacivicin and Peptidylphenylenediamine Mustard , J. Med. Chem. 1983, 26, 633-638. 

Many drugs used in cancer chemotherapy inhibit DNA synthesis or function... 

Donald Woods discovered that sulphonamides exerted their action by inhibiting an enzyme used by bacteria to synthesise folic acid. The compound 4-aminobenzoic acid is the precursor for folic acid, and is structurally similar to sulphonamide. Bacteria that were unable to synthesise folic acid were unable to achieve de novo synthesis of purines for their DNA and RNA synthesis and hence could not proliferate. Such competitive inhibitors, which mimicked normal metabolites, became known as antimetabolites (many are used in cancer chemotherapy. Chapter 21). 

Cytotoxic agents Since proliferation of cells is essential for the immune response, agents that inhibit DNA synthesis have been used as immunosuppressive agents for many years. The first were used in the 1960s, particularly to prevent rejection of a transplanted organ, for example purine and pyrimidine analogues. These agents are not now used in autoimmune diseases but are stiU used in cancer chemotherapy (Chapter 21). 

Mo, H., and Elson, C.E., Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention, Exp. Biol Med. (Maywood), 229, 567, 2004. 

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both cause DNA strand scission and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin. 

T There are several distinct types of inhibitors of nucleotide biosynthesis, each type acting at different points in the pathways to purine or pyrimidine nucleotides. All these inhibitors are very toxic to cells, especially rapidly growing cells, such as those of tumors or bacteria, because interruption of the supply of nucleotides seriously limits the cell s capacity to synthesize the nucleic acids necessary for protein synthesis and cell replication. In some cases, the toxic effect of such inhibitors makes them useful in cancer chemotherapy or in the treatment of bacterial infections. However, some of these agents can also damage the rapidly replicating cells of the intestinal tract and bone marrow. This danger imposes limits on the doses that can be used safely. 

Anemia. Testosterone and similar compounds are potent stimulators of erythropoietin synthesis from the kidneys and other tissues.109 Erythropoietin, in turn, stimulates production of red blood cell synthesis in bone marrow. Human erythropoietin, however, can now be synthesized using recombinant DNA techniques. Hence, various types of anemia that occur secondary to renal disease, cancer chemotherapy, and so forth are usually treated directly with recombinant erythropoietin.109 Nonetheless, androgens may be used as an adjunct to erythropoietin and other drugs to stimulate red blood cell production in certain patients with severe or recalcitrant anemia.10... 

Mechanism of Action. Although the exact mechanism of azathioprine is unknown, this drug probably interferes with DNA synthesis in cells mediating the immune response. Azathioprine appears to act like the antimetabolite drugs used in cancer chemotherapy (see Chapter 36). The cell normally uses various endogenous substances such as purines as ingredients... 

The opium alkaloids codeine and morphine served as models for the synthesis of naloxone, an important analog used to treat and diagnose opiate addicts, and also led to the discovery of endogenous opioids (enkephalins and endorphins) (see Chapter 47). Similarly, A9-tetrahydro-cannabinol (THC), the component of Cannabis sativa responsible for the central nervous system (CNS) effect, has also been found to reduce nausea associated with cancer chemotherapy (see Chapter 18). 

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