Podophyllotoxin-derivatives Etoposide

Extensive structure modulations were performed to obtain more potent and less toxic anti-cancer agents, such as etoposide used in the therapy of numerous cancers (Fig. 41) [113], In contrast to podophyllotoxin, etoposide derivatives act as DNA topoisomerase II inhibitors. Tafluposide (F 11782) is an etoposide where both hydroxyl functions of the glycoside moiety are acylated with the pen-tafluorophenoxyacetic acid (Fig. 41). It has been demonstrated that tafiuposide does not act as a pro-drug of etoposide, but through a specific mechanism of interaction with both topoisomerases I and lla [114]. 

Induction of strand breakage may result from inhibition of topoisomerase. The epi-podophyllotoxins etoposide and tenoposide interact with topoisomerase II, which functions to split, transpose, and reseal DNA strands (p.276) these agents cause strand breakage by inhibiting resealing. The te-cans topotecan and irinotecan are derivatives of camptothecin from the fruits of a Chinese tree (Camptotheca acuminata). They inhibit topoisomerase I, which induces breaks in single-strand DNA. 

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. 

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). 

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. 

Etoposide (XV) is a semisynthetic gylcoside derivative of podophyllotoxin, which is one of the most extensively used anticancer drugs in the treatment of various types of tumors [64,65]. The anticancer activity of this drug is mainly due to its ability to inhibit an ubiquitous and essential enzyme human DNA topo II [66,67]. Despite its extensive use in the treatment of cancers, it has several limitations, such as poor water solubility, drug resistance, metabolic inactivation, myelosuppression, and toxicity [68]. In order to overcome these... 

Two derivatives of podophyllotoxin (38), etoposide (39) and tenipo-side (40), are further examples of the use of a natural product as a drug lead. In 1890, podophyllotoxin was isolated from Podophyllumpeltatum L. (American May Apple), and in 1948, it was shown to have antineoplastic activity in mice bearing tumors. Then, hundreds of podophyllotoxin... 

Etoposide (VePesid) is a semisynthetic derivative of podophyllotoxin that is produced in the roots of the American mandrake, or May apple. Unlike podophyllotoxin and vinca alkaloids, etoposide does not bind to microtubules. It forms a complex with the enzyme topoiso-merase II, which results in a single-strand breakage of DNA. It is most lethal to cells in the S- and Gj-phases of the cell cycle. Drug resistance to etoposide is thought to be caused by decreased cellular drug accumulation. 

Podophyllotoxin 1 and its derivative etoposide 2, derived from natural sources, are in current clinical use. Michael Sherbum of Australian National University reports (J. Am. Chem. Soc. 125 ... 

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. 

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. 

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). 

Reversible alopecia is very common at standard doses of podophyllotoxin derivatives, starting at doses of 500 mg/ m of etoposide. It is also common even with low, continuous oral doses of etoposide (for example 50 mg/m / day). Partial or complete alopecia occurs in 12-70% of patients taking topotecan or irinotecan (123). 

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. 

Important drugs have been derived from two plants common in the woodlands of the eastern United States. One is etoposide (an anticancer drug) based on the podophyllotoxin found in Podophyllum peltatum,415 The second is sanguinarine (from Sangulnarla canadensis), which is used for treatment of periodontal disease. A common fence lizard of the western United States, Sceloporus occidentalis, has something in the blood that kills the bacteria responsible for Lyme disease.416... 

Podophyllotoxin is extracted from the mandrake plant. Podophyllum peltatum. A derivative of this chemical, etoposide, is used in small cell lung cancer, lymphoma and testicular cancer. The mode of action of etoposide is not completely known, but it may be due to an inhibitory effect on topoisomerase similar to that of doxombicin (see above). 

Etoposide is a podophyllotoxin derivative. Its main effect appears to be at the G2 portion of the cell cycle. At high concentrations (10 mcg/mL or more), lysis of cells entering mitosis is seen at low concentrations (0.3 to 10 meg/ mL), cells are inhibited from entering prophase. Predominant macromolecular effect appears to be DNA synthesis inhibition. Etoposide is indicated in refractory testicular tumors, and smaU-ceU lung cancer. 

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