Podophyllotoxin derivatives

Isochromones lose carbon dioxide on heating via retro-Diels-Alder pathway to result in o-quinodimethanes (equation 81)1241,129. An isochromone route to podophyllotoxin derivative has been described (equation 82)130. Diels-Alder adducts of a-pyrone readily extrude carbon dioxide on thermal activation to furnish cyclohexadienes, which are useful substrates in tandem Diels-Alder reactions (equation 83)131. 

The third acetal linkage is not so obvions, and it is in the five-membered ring fused onto the aromatic ring of the podophyllotoxin derivative. This is called a methylenedioxy group, and it is a common bidentate substitnent on many natural aromatic structures. However, it can be formally regarded as an acetal of formaldehyde. 

Tu SJ, Zhang Y, Zhang JY, Jiang B, Jia RH, Zhang JP, Ji SJ (2006) A simple procedure for the synthesis of 4-aza-podophyllotoxin derivatives in water under microwave irradiation conditions. Synlett 2785-2790... 

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. 

An important shikimate metabolite is podophyllotoxin, an antitumour compound—some podophyllotoxin derivatives are used to combat lung cancer. The compound can be split up notion-ally into two shikimate-derived fragments (shown in red and green). Both are quite different and therejjs obviously a lot of chemistry to do after-the shikimic acid pathway is finished. 

To obtain the high-pure compounds from the candidate total extracts, column chromatographic separation is performed for some illustrative total extracts. For example, squalene and podophyllotoxin with high purity are isolated from the related extracts. Upon comparison with the LSE, we found that squalene can be easily obtained from the SFE extract than the case of LSE. Although we are not shown here similar interesting results are obtained for other substances. For example, high-purity podophyllotoxin derivatives, which has been known for antitumor activity[4] can be obtained easily from the SFE extract of Podophyllum peltatum. 

Table 1 Selected podophyllotoxin derivatives prepared by reacting 4 -0-demethyl-4p-4-desoxypodphylotoxm and heterocyclic amines and their corresponding physical data. H-NMR for products supplied by author.

Table 2 Cytotoxity of selected podophyllotoxin derivatives against KB cells and cellular protein-linked DNA breaks...

Benzoyl-anilino podophyllotoxin derivatives, (III), prepared by Kamal (2) and carbamate and thiocarbamate derivatives, (IV), prepared by Monneret (3), respectively, were effective against murine leukemia from L1210 cells. 

You Y. Podophyllotoxin derivatives current synthetic approaches for new anticancer agents. Curr. Pharm. Des. 2005 11 1695-1717. 

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). 

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). 

Difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoic acid 4,ll-bis[(2-Aminoethyl)amino]anthra[2,3-b]furan-5,10-diones 4(l-Anilino-podophyllotoxin derivatives 5-Aza-2 -deoxycytidine 5-Bromotetrandrine 5-Cyclohexylindolyl-2 -deoxyribose (non-natural nucleoside) 5 -Fluorosulfonylbenzoyl 5 -adenosine 5-Fluorouracil 5,5-Diphenylbarbituric acid 6-[(2S,4R,6E)-4-Methyl-2-(methylamino)-3-oxo-6-octenoic acid] cyclosporine D (PSC833) 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid 6-Mercaptopurine 6-Prenylchrysin 6-Thioguanine 6,7-Dimethoxy-... 

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. 

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. 

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). 

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