Antimetabolites antitumor

The pyrimidine 5-fluorouracil (64) is used extensively in the clinic as an antimetabolite antitumor agent. As a consequence of poor absorption by the oral route, the drug is usually administered by the intravenous route. A rather simple latent ated derivative, tegafur (66), has overcome this limitation by providing good oral absorption. Reaction of 5-fluorouracil with trimethylsilyl chloride in the presence of base gives the disilylated derivative (65). Reaction of this with dihydrofuran (obtained by dehydro-... 

Drugs that require metabolic activation for antitumor activity, such as the antimetabolites 5-fluorouracil and 6-mercaptopurine, may be ineffective if a tumor is deficient in the required activating enzymes. Alter-... 

Mercapto-4-amino-5-carbethoxypyrimidine has been converted to 2-methylmercapto-4-amino-5-hydroxymethylpyrimi-dine,6 an antimetabolite possessing antitumor activity,7 by methylation of the mercapto group followed by reduction of the ester group to a hydroxymethyl group with lithium aluminum hydride.6... 

There are several antitumor antibiotics resembling the synthetic nucleoside antimetabolites discussed on p. 160. They are adenine derivatives with unusual furanose compounds attached to the 9-position. Psicofuranine (54) is an example. The rather more complex example puromycin (55) is also active against trypanosomes and Gram-positive bacteria. Tubercidin (56) and two related antibiotics have an altered purine system. 

The three principal classes of cytotoxic agents used in the treatment of cancer all contain carcinogens, for example, Melphalen, a nitrogen mustard, adriamycin, an antitumor antibiotic, and methotrexate, an antimetabolite. Diethylstilbestrol (DES), a drug formerly widely used, has been associated with cancer of the cervix and vagina in the offspring of treated women. 

Antimetabolites of nucleic acids as antitumor agents 91YGK989. Artemisinine (3,6,9-trimethyl-9,10h-epidioxyperhydropyrano[4,3,2-y/c] benzoxepin-2-one), a new type of antimalarial drug 92CSR85. 

After the formulation of the antimetabolite theory by Woods and Fildcs in 1940,antimetabolites based on a variety of known nutrients were prepared. The first purine analogue to show antitumor activity in mice. 8-azaguanine. was synthesized by Roblin in I94. i. This compound was intro-... 

Finally, it may be worthwhile to point out that one of the most successful chemotherapeutic drugs provided by nature may be considered as a non-classical active-site-directed irreversible inhibitor This drug is penicillin (70). As a non-classical antimetabolite of D-alanyl-D-alanine, it first forms a reversible complex with the enzyme peptidoglycan transpeptidase, and then by a ringopening reaction of its p-lactam moiety, it forms a covalently linked penicil-loyl-enzyme complex97. However, the reaction involves the acylation of a sulfhydryl group in the active site of the enzyme in this respect, 70 resembles the classical-type endoalkylating antimetabolites, azaserine and DON (8 and 9, see Section 2.2.). Some of the more recently discovered antibiotics and natural products from plants with antitumor activity (e.g., camptothecin) are... 

Polymer (VI) has been shown to have antitumor activity against adenocarcinoma 755, Dunning ascites leukemia. Friend leukemia virus, and Lewis lung carcinoma. In the latter case, polymer (VI) showed activity about equal to that of cyclophosphamide (an alkylating agent) and was more effective than 6-mercaptopurine (an antimetabolite) ( ). The DIVEMA polymer (V) Is also active against some cancer causing viruses such as Friend leukemia, Moloney sarcoma and Rauscher leukemia ( ). 

Cladribine (2-chlorodeoxyadenosine 2-CDA) is a purine nucleoside analog that is resistant to inactivation by adenosine deaminase. The triphosphate form of this agent is incorporated into DNA, resulting in inhibition of DNA synthesis and early chain termination. Cladribine s antitumor activity is unusual for an antimetabolite in that it affects both actively dividing and resting cancer cells. Like fludarabine, cladribine possesses immunosuppressive effects that place patients at risk for serious opportunistic infections. ... 

Contents E.J.Ariens, A.-M.Simonis Design of Bioactive Compounds. -T.J.Bardos Antimetabolites Molecular Approaches for Designing Antiviral and Antitumor Compounds. -T.A.Connors Alkylating Agents. -E.De Clercq Synthetic Interferon Inducers. - C.Woenckhaus Synthesis and Properties of Some New NAD Analogues. 

NDGA has been shown to have antitumor activity in vivo and in vitro. It is a powerful cancer antimetabolite producing in vitro complete inhibition of aerobic and anaerobic glycolysis and respiration of suspensions of several types of tumor cells including leukemia types. In vivo, NDGA combined with ascorbic acid is reported to reduce... 

Antimetabolites and Antitumor Peptides Peptides from Fungi... 

A number of peptides of animal origin were shown to play a role in cancer therapy as antimetabolites. Later, several peptide antibiotics were demonstrated to have similar properties. One of these, cyclosporin A (5), produced by certain fungi imperfecti, was shown to prevent attack on host tissues by transplanted cells (Sneader, 1985). Another series of peptides from Streptomyces verticillus, of which bleomycin A2 (Fig. 14.2) is the main component used clinically, has pronounced antitumor activity. The most striking feature... 

The ubiquitous distribution of both MTs and stress proteins may be exploited in cancer therapy regimens. MT may serve as an adjunct in cancer chemotherapy (Imura et al. 1991 Cherian et al. 1994). The selective induction of MT by bismuth in noncancer cells protects these cells from harmful side effects of a number of chemotherapeutics, including alkylating agents, antimetabolites, and mitotic inhibitors, but does not interfere with the efficacy of these compounds. Conversely, the presence of MT in tumors may act as a multidrug resistance factor in cancer chemotherapy (Cherian et al. 1994). While the role of stress proteins is not clearly defined, hyperthermia potentiates the antitumor effects of chemotherapeutics and radiotherapy (Nover 1991). 

---