Podophyllo toxin

The one-bond HETCOR spectrum and C-NMR data of podophyllo-toxin are shown. The one-bond heteronuclear shift correlations can readily be made from the HETCOR spectrum by locating the posidons of the cross-peaks and the corresponding 5h and 8c chemical shift values. The H-NMR chemical shifts are labeled on the structure. Assign the C-NMR resonances to the various protonated carbons based on the heteronuclear correlations in the HETCOR spectrum. 

The heteronuclear multiple-quantum coherence (HMQC) spectrum, H-NMR chemical shift assignments, and C-NMR data of podophyllo-toxin are shown. Determine the chemical shifts of various carbons and connected protons. The HMQC spectra provide information about the one-bond correlations of protons and attached carbons. These spectra are fairly straightforward to interpret The correlations are made by noting the position of each crossf)eak and identifying the corresponding 8h and 8c values. Based on this technique, interpret the following spectrum. 

The nOe difference and ID H-NMR spectra (in C5D5N) of podophyllo-toxin are shown. Justify the stereochemical assignments of the C-2, C-3, and C-4 asymmetric centers based on the nOe data, assuming that the C-4 proton is -oriented.. ... 

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... 

Cortese F, BhattacharyyaB, Wolff J, Podophyllo toxin as a probe for the colchicine binding site of tubulin, /5zh/ Chem 252 1134—1140, 1977. 

Puri SG, Nazir A, Ghawla R, Arora R, Riyaz-ul-Hasan S, Amna T, Ahmed B, Verma V, Singh S, Sagar R, Sharma A, Kumar R, Sharma RK, Ghulam NQ, The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllo-toxin and related aryl tetralin Yign2isi, J Biotechnol 122 494-510, 2006. 

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... 

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). 

The mechanism of actions involves tubulin binding, reverse transcriptase inhibition, integrase inhibition and topoisomerase inhibition. Podophyllo-toxins bind to tubulin and are able to disrupt the cellular cytoskeleton and interfere with some vital virus processes. There is no relationship between the inhibition of reverse transcriptase (RT) and chemical structure in the case of lignans, because all the chemical antiviral structures are able to bind to the enzyme. As to the rest of the mechanism, there is not much information available. The effects of rabdosiin may be due to its topoisomerase inhibitory effects. Charlton concluded that the antiviral activity of lignans is not strong and that except for podophyllotoxin, which is used topically to treat various warts caused by HPV, none of them are of interest for commercial application. 

Podophyllotoxin (5./7), from Podophyllum peltatum, the tropical squirting cucumber , strongly inhibits the polymerization of tubulin and is used in dermatology to destroy warts and other skin neoplasms. Deoxy-podophyllo-toxin, from the berries of the juniper tree, has anti-viral activity. Etoposide, a semi-synthetic derivative of podophyllotoxin, is used clinically for the treatment of otherwise fatal tumours. Chemically it is demethyl-1-0-(4,6-0-ethylidene-)8-D-glucopyranosyl)epipodophyllotoxin. It does not seem to prevent the synthesis of microtubules, but a decrease in DNA synthesis is noted (Loike, 1984). 

Beutner KR, von Krogh G (1990) Current status of podophyllo-toxin for the treatment of genital warts. Semin Dermatol 9 148-151... 

We next turned our attention to the 1-arylnaphthalene and tetralin lignans (Fig, 13) which include podophyllo-toxin and many other important lignans, A model biomimetic sequence is shown in Scheme 20, This can be combined with tandem addition process to butenolide (vide infra), More generally our approach was to use butenolide as an example of a C -unit with opposite charges on adjacent carbon atoms (Scheme 21). As a model we used a dithane anion as the nucleophile and a benzyl bromide as the electrophile in tandem addition to butenolide. The reaction worked well to give the trans-fused product This seems... 

VP 16-213 (SED VIII, p. 979) is a semisynthetic product derived from podophyllo-toxin. The toxicity of oral VP16 has been documented in some detail (17 ) and shows that many of the side effects are dose-related. The following complications were recorded nausea, vomiting, stomatitis, diarrhoea, anaemia, leukopenia, thrombocytopenia, pruritis, alopecia, substemal discomfort and peripheral neuritis. The last complication was only seen in patients treated with 300—400 mg/day, orally for 5 days with a rest period of 9 days between courses. A similar range of toxicities has been reported by other authors (33, 74, 60, 79). 

Qinical trial of the oral form of a new podophyllo toxin derivative VP16-213 (NSC-141540) in patients with advanced neoplastic disease. Cancer Chemother. Rep., 59, 1027. 

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