Podophyllotoxin-derivatives Teniposide

Teniposide is a podophyllotoxin derivative. Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G2 phase of the cell cycle, thus preventing cells from entering mitosis. Teniposide causes single- and double-stranded breaks in DNA and DNA protein cross-links. The mechanism of action appears to be related to the inhibition of type II topoisomerase activity. The terminal half-life is 5 hours. The volume of distribution is 3 to 11 L in children and 8 to 44 L in adults. Renal elimination is 44%, fecal elimination is up to 10%, and 4 to 12% is excreted unchanged in the urine. Adult used in refractory childhood acute lymphoblastic leukemia. Pediatric used in refractory acute lymphoblastic leukemia (ALL). 

Although not listed in the tables, at least four other natural product drugs have given yeoman service in the antitumor area. The first of these is paclitaxel (Taxol ) which sold US 1.6 billion in 2000 this is followed by the vinca alkaloids vinblastine and vincristine. Completing the quartet are the natural product-derived epi-podophyllotoxin derivatives teniposide and etoposide and the materials derived from camptothecin, topotecan and CPT-11. These will probably not be the only natural product drugs in the antitumor field, as can be seen by inspection of Table 6.3, where Cragg and Newman recently reported on the source... 

As reported by Apers et al. [89], podophyllotoxin derivatives can be divided into two groups in terms of their mechanism of action 1 Inhibitors of tubulin polymerization (such as podophyllotoxin), 2 Inhibitors of DNA topoisomerase II (such as etoposide and teniposide). Combining both pharmacophores leads to compounds with a dual mechanism of action, such as azatoxin. 

Skin rashes due to podophyllotoxin derivatives may be hypersensitivity reactions and can be related to the drug itself or more commonly to the vehicles used. Dose-related, non-IgE-mediated hypersensitivity has been reported in 16 children receiving teniposide (118). Other published reports of hypersensitivity or anaphylactoid reactions to teniposide include degranulation of basophils (119,120), and eight anaphylactic reactions in children, all associated with the use of intravenous teniposide 150 mg/ m (121). 

Etoposide and teniposide are semisynthetic podophyllotoxin derivatives (see Table 124-13). Podophyllin is extracted from the mayapple or mandrake plant. Like the vinca alkaloids, podophyllin itself binds to tubulin and interferes with microtubule formation. Unlike the parent compound, however, etoposide and teniposide damage tumor cells by causing strand breakage through inhibiting topoisomerase Resistance may be caused by differences in topoisomerase II levels, by increased cell ability to repair strand breaks, or by increased levels of P-glycoproteins. Etoposide and teniposide are usually clinically cross-resistant. They are cell-cycle phase-specific and arrest cells in... 

Podophyllotoxin (1) inhibits the assembly of microtubulin and the activity of topo-isomerase II, and exhibits strong antitumor activity. It is considered as the critical structure of antitumor compounds. Since the 1940s, many podophyllotoxin derivatives have been synthesized. Among them, etoposide (VP-16-213,65) and teniposide (VM-26, 66) exhibit no gastrointestinal toxicity, and have been used with cisplatin (ciY-diaminodichloroplatinum) in human chemotherapy. Compound 66 is more potent than 65 in L-1210 and HeLa tumor cell lines, and shows strong activity in hematological malignancies. 

The in vitro cytotoxicity of 5-methoxypodophyllotoxin, obtained from a root culture derived from Linum flavum, against EAT and HeLa cells was determined and compared with those of podophyllotoxin, etoposide, teniposide and 5-methoxypodophyllotoxin-4- 3-D-glucoside [106]. The tested lignans had about the same cytotoxic potency as podophyllotoxin (ED50 of 32 and 22 pg/mL versus 42.8 and 20.5 pg/mL, respectively against EAT and HeLa cells). However, in comparison with etoposide and teniposide they were clearly less potent (1.1 and 7.9 pg/mL, and 0.06 and 0.3 pg/mL, respectively). 

Closely related to Teniposide, T-17. Semisynthetic podophyllotoxin deriv. DNA topoi-somerase II inhibitor. Antineoplastic agent. Marketed drug. Cryst. (MeOH). 

A semisynthetic podophyllotoxin derivative, VP 16213 (etoposide), has been approved in the United States as a chemotherapeutic agent (often in combination regimes with cisplatin, bleomycin, and others) for the treatment of refractory testicular tumors and for the treatment of small cell lung cancer. VM26 (teniposide) is being investigated for the treatment of acute lymphoblastic leukemia, various lymphomas, and other carcinomas. Semisynthetic derivatives are being used in Europe for the treatment of psoriasis and rheumatoid arthritis. 

In the anticancer area, the use of natural products as direct agents or as novel lead compounds for the generation of synthetic or semisynthetic analogs has proved remarkably productive, and a recent survey showed that 62% of new anticancer agents over the last 10 years have been natural products or agents based on natural product models.7 Examples of clinically important plant-derived natural products are the vinca alkaloids vinblastine (4) and vincristine (5), the podophyllotoxin analogs etoposide (6) and teniposide (7), the diterpenoid paclitaxel (Taxol ) (8), and the camptothedn-derivative topotecan (9). 

In many cases the isolated natural product may not be an effective drug for any of several possible reasons, but it may nevertheless have a novel pharmacophore. In such cases chemical modification of the natural product structure, either by direct modification of the natural product (semisynthesis) or by total synthesis, can often yield clinically useful drugs. Examples of this from the anticancer area are the drugs etoposide, teniposide, and topote-can, derived from the lead compounds podophyllotoxin and campothecin. 

Podophyllotoxin, a potentially lethal component of mayapple, blocks cell division and has tumor-inhibiting properties. Two drugs derived from it are approved for use in the U.S. Etoposide is used to treat testicular and small-cell lung cancer. Teniposide is employed with brain tumors and childhood leukemia (see Chapter 62). 

Two compounds, VP-16 (etoposide) and a related drug, VM-26 (teniposide), are semisynthetic derivatives of podophyllotoxin, which is extracted from the mayapple root (Podophyllum peltatum). Both an intravenous and an oral formulation of etoposide are approved for clinical use in the USA. 

The best example of a lignan used as a lead compound is podophyllotoxin, an antimitotic compound that binds to tubulin, although podophyllotoxin has not been isolated from Taxus species,. Etoposide and teniposide are well-known compounds derived from podophyllotoxin, and their antitumor activity is due to the inhibition of topoisomerase II. 

Teniposide undergoes more extensive metabolic degradation than etoposide, resulting in the catechol derivative 4 -demethyldeoxy-podophyllotoxin. The aglycone and the trans/cis-hydroxy acids appear to be formed by pH-dependent hydrolysis reactions (7,95,96). 

The anti-neoplastic activity of podophyllotoxin and derivatives has prompted continuous development into clinical agents for treatment of human neoplasia. The semi-synthetic 4 -demethylepipodophyllotoxin derivatives, Etoposide (139) and Teniposide (140). developed by a Sandoz (Basel) group have attracted considerable attention (135-137) (Scheme 28). They have established antitumour activity with lesser toxicity and mechanism of action differing from podophylloxin itself. 

Abstract Podophyllotoxin glucoside derivatives (Etoposide, Teniposide etc.) were synthesized from Podohyllotoxin by 5 steps of reactions. The method has many advantages, such as no need of protecting 4 -hydroxy, decrease of 2 reactions, and increase of more than 10% in total yield, in comparison with the conventional process. In this paper, alcoholysis reaction conditions were carefrilly studied and 5 metals as catalytic agent were selected. The new alcoholysis reaction is characterized by simple procedures, good quality and high yield. 

Compound (VI) were prepared by reacting compound ( I) with aldehyde in the presence of lewis acids at 20X under protection and protecting in N2. A lot of podophyllotoxin glucoside derivatives such as Meoposide, Teniposide, Etoposide and SP-G ect. were prepared by this method. 

Natural products have a history of providing novel, clinically useful anticancer drugs and a number of these have come from higher plants (ref. 1-21). In addition, many of these compounds have served as prototypes for the development of novel analogs of clinical importance. Some specific examples are colchicine (ref. 22) and its derivatives, the podophyllotoxins (ref. 23) including the clinically-effective epipodophyllotoxin derivatives etoposide and teniposide (ref. 24), and the Vinca alkaloids, vincristine, vinblastine, and vindesine (ref. 25,26). More recently indicine N-oxide, homoharringtonine and taxol have entered clinical trials (ref. 13,21). The discovery of natural products with potential as anticancer drugs has recently been reemphasized by the NCI. 

So much attention has been paid to podophyllotoxin and its derivatives, that the details cannot be considered here. Etoposide (VP-16), and teniposide (VM-26), 22, are used clinically in the treatment of human cancers and their action has been compared with that of podophyllotoxin, (Fig. 9). It suffices to say that, although podophyllotoxin is closely related to VP-16 and VM-26, uniquely they affect cells by entirely different modes of action.Podophyllotoxin behaves like colchicine, 24, and 3-peltatin, 23, in binding to tubulin, although colchicine and podophyllotoxin occupy adjacent sites rather than the same site.VP-16 and VM-26 are inactive in the inhibition of microtubule formation but inhibit DNA synthesis. 

Numerous analogs of epi-podophyllotoxin, bearing amine and ether substituents at C4 have been reported. Several of these semi-synthetic drugs derived from podophyllotoxin, including etoposide and teniposide, are used clinically in cancer therapy. 

Podophyllotoxin 3 is a naturally occurring antitumor antibiotic . Attempts to reduce the toxicity have resulted in the synthesis of glucosidic phenolic derivatives, VP-16 (etoposide, a semisynthetic analog) 4a and VM-26 (teniposide) 4b. Their mode of action is thought to be associated with DNA breakage . Haim et al. proposed a mechanistic pathway entailing oxidation with subsequent 0-demethylation to form the o-quinone metabolite 5a (Equation 2). In vivo conversion of methoxyl to hydroxyl has been previously observed . Electrochemical oxidation of VP-16 and other methoxyphenols also leads to quinone products. 

Podophyllotoxin 87, isolated from Podophyllum species shows antitumor properties it inhibits microtubule assembly, in vivo, the result of which is the destruction of the cytoskeleton in the cytoplasm. As a consequence, the cell division is stopped at the mitotic stage of the cell cycle (3), Semi-synthetic derivatives of podophyllotoxin, i.e., Etoposide 88 and Teniposide 89 have been developed. Tliey do not possess the toxicity of podophyllotoxin 87 and are now being used (alone or in conjunction with odier drugs) in treatment for germinal testicular cancer, small cell lung cancer, and certain form of leukemia (3), They have been shown to induce, both, in... 

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