Etoposide, structure

The vinca alkaloids vinblastine and vincristine are capable of producing the MDR phenotype in a wide variety of cell types. Furthermore, cells that are made resistant to antitumor drugs such as doxorubicin, actinomy-cin D, or the epipodophyllotoxins etoposide (VP-16) and teniposide (VM-26) are often resistant to the effects of the bisindole alkaloids. The structural and mechanistic diversity of these compounds is even more striking against the backdrop of collateral resistance. 

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. 

Teniposide (VM-26, Vumon) is closely related to etoposide in structure, mechanisms of action and resistance,... 

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]. 

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. 

Rappa G, Shyam K, Lorico A et al (2000) Structure-activity studies of novobiocin analogs as modulators of the cytotoxicity of etoposide (VP-16). Oncol Res 12 113-119... 

Wen Z, Tallman MN, Ali SY, et al. UDP-glucuronosyltransferase 1A1 is the principal enzyme responsible for etoposide glucuronidation in human liver and intestinal microsomes structural characterization of phenolic and alcoholic glu-curonides of etoposide and estimation of enzyme kinetics. Drug Metab Dispos 2007 35(3) 371-380. 

There is a high level of expression of P-gp in the epithelial cells of the small intestine. Compounds that have been found to be substrates exhibit a wide range of chemical structures. However, they tend to be lipophilic and, for some, cationic, such as anthracyclines, vinca alkaloids, cyclosporin, etoposide, and celiprolol. It has been shown that taxol, an anti-microtubule anticancer drag, was not absorbed after oral administration in pre-clinical trials. This can probably be attributed to P-gp, since the flux from the... 

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... 

Figure 13.2 Structures of a doxorubicin, b mitoxantrone, c topotecan and d etoposide.

Figure 9 Structures of podophyllotoxin, etoposide, teniposide, etopophos, daunorubicin, and doxorubicin.

In contrast, the structurally related etoposide phosphate is highly soluble in aqueous solutions and no solubilizing adjuvants are necessary. Preliminary data suggest that the incidence of hypersensitivity reactions is lower with etoposide phosphate than with etoposide, strengthening the hypothesis that adjuvants have a major role in the development of allergic reactions (123,124). In one case, a patient who had a type I hypersensitivity reaction to etoposide was successfully retreated with etoposide phosphate (134). 

Fig-1 Structures of naringenin (flavanone, 1), naringin (flavanone O-glycoside, 2) and rutin (flavonol O-glycoside, 3), ketoconazole (4), 7/3-hydroxycholesterol (5) and 25-hydroxycholesterol (6), resveratrol (7) and etoposide (8, VP-16)... 

Etoposide p-gp [140] Sorivudine Nucleoside Structural analogy to zidovudine... 

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. 

Studies of the structure-activity relationship of Cl-substituted derivatives of etoposide, albeit few, have shed light on the relative importance of the nature of the substitution. Most compounds generated have either a hydroxyl or a methoxy group at C4 of the aromatic E ring. Analysis of the biological activity of these compounds has clearly demonstrated that... 

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