Etoposide derivatives

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]. 

The synthesis and biological evaluation of etoposide derivatives has been a primary research focus of my laboratory for many years. Some highlights of this research follow, and this work illustrates several aspects of the drug development process as described in the introduction. 

Epipodophyllotoxins (etoposide, teniposide) are derived from mandrake root (Podophyllum peltatum). They inhibit topoisomerase H thus causing double strand breaks. Cells in S- and G2-phases are most sensitive. Unwanted effects include nausea and vomiting, myelosuppression, and hair loss. 

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... 

Examples of inhibitors of chromatin function derived from flowering plants (Fig. 80) are etoposide (lignan) and alkaloids camptothecin, Vinca alkaloids, and 7 epitaxol. The rhizome of Podophyllum peltatum L. (May apple, Berberidaceae) has been used to remove warts and to relieve the bowels from costiveness since very early times. It contains podophyllo-toxin, a cytotoxic lignan from which etoposide (Vepesid ), which is used to treat lung cancer, lymphomas, and leukemias on account of its ability to inhibit the activity of... 

UGTIAI has an important role in the metabolism of irinotecan, etoposide, epiru-bicine, and tipifamib. Irinotecan is a camptothecin derivative used in the treatment of metastatic colon cancer. Irinotecan is a prodrug since it is activated to Ethyl-10-hydroxycamptothecin (SN-38) by carboxyl esterase to exert its antitumor activity mediated by the inhibition of topoisomerase I. SN-38 undergoes UGTIAI-catalyzed glucuronide conjugation to form the inactive SN-38 glucuronide (SN-38G). 

In recent years, however, some of the greatest emphasis has been placed on the search for anticancer and antiviral agents derived from natural products. Success in that area has not heen as great as that achieved in other helds. Since 1960, only seven plant-derived drugs have heen approved by the FDA for use as anticancer agents. Four of those drugs, vinblastine, vincristine, etoposide, and teniposide, were discovered in the 1950s. The last three—Taxol , topotecan, and irinotecan—were discovered and approved much more recently. 

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 and teniposide are synthetic derivatives of the extract of the American mandragora plant (May Apple). The mechanism of their action has not been completely explained however, they act on the enzyme topoisomerase II, which disturbs the twisting of DNA. In addition, they inhibit DNA and RNA synthesis, as well as transport of nucleotides to cells. Cytotoxic action on normal cells is observed only in very high doses. These drugs exhibit significant activity in lymphomas, leukemia, Kaposi s sarcomas, and in testicular cancer. 

The topoisomerase II inhibitors etoposide and teni-poside are semisynthetic derivatives of podophyllo-toxin. They form a complex with topoisomerase II and DNA which results in double-stranded DNA... 

Three classes of plant-derived drugs, the vinca alkaloids (vincristine, vinblastine, and vinorelbine), the epipodo-phyllotoxins (etoposide and teniposide and the tax-anes (paclitaxel and taxotere), are used in cancer chemotherapy. These classes differ in their structures and mechanisms of action but share the multidrug resistance mechanism, since they are all substrates for the multidrug transporter P-glycoprotein. 

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. 

As with ciimolines, phthalazines were also prepared most frequently through condensations of hydrazine derivatives and carbonyl-containing compounds. For example, Monneret and co-workers reported the condensation of dialdehyde 148 with hydrazine to produce phthalazine derivative 149, an advanced intermediate in the preparation of anticancer analogs of etoposide <99T12805>. 

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. 

Since 1961, nine plant-derived compounds have been approved for use as anticancer drugs in the U.S. vinblastine (Velban), vincristine (Oncovin), etoposide (VP-16,1), teniposide... 

Etoposide and teniposide derivatives Lundberg (1994) Enhanced solubilization, cellular uptake, and cytotoxic activity of lipophilic prodrugs... 

Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

Another area in which natural products have had a major impact on longevity and quality of life is in the chemotherapy of cancer. In fact, most major anticancer drugs are derived from plants or microorganisms (see Chapter 62). Examples include bleomycin, doxorubicin, daunorubicin, vincristine, vinblastine, mitomycin, streptozocin, and most recently, additions of paclitaxel (Taxol ), ironotecan (a camptothecin derivative), and etoposide and tenoposide (podophyllo-toxin derivatives). 

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. 

Drugs used in cancer chemotherapy are cytotoxic drugs, hormones, plant derivatives, radioactive isotopes, and miscellaneous agents (e.g., procarbazine, hydroxyurea, mitotane). The plant-based drugs vincristine, vinblastine, vinorel-bine, etoposide, and campothecins. Radioactive isotopes, such as 131 iodine (131 I), are used in the treatment of thyroid tumors. Cytotoxic drugs (e.g., cis-platin, cyclophosphamide, 6-mercaptopurine, 5-fluorouracil, and methotrexate are used for the treatment of cancer. 

Topotecan (toe poe TEA can) has recently been approved for the treatment of metastic ovarian cancer. It is a semi-synthetic derivative of an earlier drug, camptothecin. Topotecan has a complicated multiring structure containing a lactone ring that is essential for activity. The drug inhibits topoisomerase I, which is essential in the replication of DNA in human cells (Figure 38.23). Unlike etoposide, which inhibits... 

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