Metabolites cytotoxicity

Alkylating agents Anti metabolites Cytotoxic antibiotics Platinum drugs Topoisomerase inhibitors... 

An intriguing application of Zincke processes occurred in Marazano s synthesis of dimeric, tetrameric, and even octameric pyridinium macrocycles, including cyclostellettamine B, a sponge-derived natural product. The same strategy produced a synthesis of haliclamine A (121, Scheme 8.4.41), a cytotoxic sponge metabolite. Intermediate 119, itself produced via a Zincke route, underwent an intramolecular Zincke reaction, providing macrocycle 120, which was reduced to the natural product. 

Benzopentathiepins are stable solids. Varacin, a cytotoxic metabolite, was isolated from a marine ascidian.398 The parent benzopentathiepin exhibits infrared absorptions at 1620, 1570, 1235 and 1020 cm" 1.399 X-ray structure analyses of benzopentathiepin and 6-methylbenzopen-talhicpin show that the seven-membered ring in both compounds is nonplanar and that it adopts a chair conformation. The S-S bond lengths are in the range 204-206 pm.400... 

According to a hypothesis launched by Larionov et al in the 1960s, some new nitrogen mustard derivatives were developed. They contain metabolites and heterocyclic structures as carriers of the cytotoxic chloroethylamine groups. By this way the synthesis of aliylating metabolites started melphalan (sarcolysine) as L- or DL-phenylalanine derivative prospidine with a tricyclic piperazine moiety and chlorambucil as butyric acid derivative. It was proven that each alkylating metabolite has its own spectrum of selective antitumor activity. 

German investigators (Brock et al) worked on the creation of alkylating pro-drugs that have cytostatic activity after specific biotransformation in the tumor tissue. Cyclophosphamide (CTX) has well pronounced antitumor activity with the broadest spectrum. It is metabolized to the cytotoxic phosphoamide mustard. In normal tissues with high enzyme level cyclophosphamide is converted to its inactive metabolites (Fig. 2). These differences in biotransformation can explain the relative selectivity of cyclophosphamide towards... 

British investigators (Haddow and Timmis 1951) synthesized and studied esters of the methanesulfonic acid. The most active derivative was the dimethylsulfonic ester of 1,4-butanedione, known as busulfan. Busulfan interacts with the thiol groups of proteins and amino acids some of its metabolites can alkylate the thiols of cysteine, peptides and proteins. Busulfan exerts selective cytotoxic activity in hematopoietic bone marrow cells and inhibits the formation of granulocytes and platelets. It slightly affects the lymphoid tissue. 

Cladribine (2-Chlordeoxyadenosine) is a synthetic purine nucleoside that is converted to an active cytotoxic metabolite by the deoxycytidine kinase. The drug is relatively selective for both normal and malignant lymphoid cells. 

By enhancing the metabolism of trichloroethylene to its cytotoxic metabolites, compounds that induce the hepatic mixed-function oxidase system can potentiate the hepatotoxicity of trichloroethylene. 

Another study showed that a mixture of oxidative metabolites of P-carotene, but not P-carotene, was able to increase the binding of benzo[a]pyrene to DNA. Other mixtures of P-carotene cleavage products have been shown to induce oxidative stress in vitro,exert cytotoxic and genotoxic effects, and inhibit gap junction intercellular communications. It has been suggested that these detrimental effects could possibly occur in vivo following the intake of high doses of carotenoids. 

Lambert M, S Kremer, H Anke (1995) Antimicrobial, phytotoxic, nematicidal, cytotoxic, and mutagenic activities of 1-hydroxypyrene, the initial metabolite in pyrene metabolism by the basidiomycete Crinipellis stipitaria. Bull Environ Contam Toxicol 55 251-257. 

Hiraishi, H., Terano, A., Ota, S., Ivey, K.J. and Sugjmoto, T. (1987). Oxygen metabolite-induced cytotoxicity to cultured rat gastric mucosal cells. Am. J. Physiol. 253, G40-G48. 

Kawabe, T., Hiraishi, H., Hata, Y., Razandi, M., Teranoa, T. and Ivey, K.J. (1992). Reactive oxygen metabolites mediate cytotoxicity to cultured colonic epithelial cells. Gastroen-terolc 102, A644. 

Daunorubicin is an anthracycline that is sometimes referred to as an antitumor antibiotic. Daunorubicin inserts between base pairs of DNA to cause structural changes in DNA however, the primary mechanism of cytotoxicity is the inhibition of topoisomerase II. The pharmacokinetics are best described by a two-compartment model, with a terminal half-life of about 20 hours. The predominant route of elimination of daunorubicin and hydroxylated metabolites is hepatobiliary... 

Manna, C. et al. (1997). The protective effect of the olive oil polyphenol (3,4-dihydroxyphenyl)-ethanol counteracts reactive oxygen metabolite-induced cytotoxicity in Caco-2 cells. J. Nutr. 127(2) 286-292. 

Mata, J. F., et al. Role of the human concentrative nucleoside transporter (hCNTl) in the cytotoxic action of 5[Prime]-deoxy-5-fluorouridine, an active intermediate metabolite of capecitabine, a novel oral anticancer drug. Mol. Pharmacol. 2001, 59, 1542— 1548. 

At cellular level, 6-MP is transformed in a number of active and inactive metabolites, and in the bone marrow, the balance between activation and inactivation of 6-MP is the main determinant of its antiproliferative effect. Similar to other antimetabolites, 6-MP is a prodrug lacking any cytotoxic activity and needs to be activated [3] (Figure 14.1). The first step is 6-MP transformation into 6-thioinosine monophosphate (6-TIMP), which is subsequently converted to 6-thioguanine tri-... 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

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