A short stereoselective formal total synthesis of podophyllotoxin has been carried out from a sulfoxide, using a onepot tandem conjugate addition aldolelectrophilic aromatic substitution reaction to form a tetralin, which was converted into picropodophyllin in two steps. Podophyllotoxin article about podophyllotoxin by the. The pharmaceutically important anticancer drugs etoposide and teniposide are derived from podophyllotoxin, a natural product isolated from roots of podophyllum hexandrum growing in the wild. Michael sherburn of australian national university reports j. It is not recommended in hpv infections without external warts. Synthesis of new tetralone intermediates for podophyllotoxin analogues dabbeghatta chikkachar umesha, yeriyur basavaiah basavaraju, basavaiah umesha department of studies in chemistry, university of mysore, manasagangotri, mysuru570 006, karnataka, india abstract podophyllotoxin is a potent antimitotic agent. The plant contains podophyllotoxin, a chemical that gave rise to its former popularity as a purgative, but a failure to address the precise dosage led. The central tetralin ring system in these derivatives was constructed by the cyclization of. Podophyllotoxin is a potent inhibitor of microtubule assembly. Podophyllotoxin is a potent inhibitor of microtubule assembly and dna topoisomerase ii.
Synthesis of podophyllotoxin and its derivatives are widely reported in literature. Sampling date also affected podophyllotoxin content. Synthesis of podophyllotoxin podophyllotoxin 1 and its derivative etoposide 2, derived from natural sources, are in current clinical use. Podophyllotoxin definition of podophyllotoxin by the. All the compounds were evaluated for their anticancer activity against a panel of five human cancer cell lines hl60, smmc7721, a549, mcf7, sw480 using mtt assays. Podophyllotoxin cream is commonly prescribed as a potent topical antiviral. The solution is derived from the roots of the podophyllum plant. Regarding their sources, berbamine is extracted from berberis vulgaris with a reported apoptosis in human myeloma cells 51, 52.
The nagorny synthesis of cannogenol and cannogenol3o. Podophyllotoxin i, a wellknown naturally occurring. Some of its less toxic derivatives, such as etoposide and teniposide, are used as antineoplastic agents. Synthesis and cytotoxicity of novel analogues of podophyllotoxin. Synthesis of podophyllotoxin aring pyridazine analogue. Abstract a short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Jan 01, 2012 podophyllotoxin abbreviated as ppt, otherwise known as podofilox, is a nonalkaloid toxin lignan extracted from the roots and rhizomes of podophyllum species. Cell division is arrested and other cellular processes are impaired, gradually resulting in the disruption of. Cell division is arrested and other cellular processes are impaired, gradually resulting in the disruption of cells and destruction of the tissue. Current synthetic approaches for new anticancer agents volume. Podophyllotoxin acts as an inhibitor of microtubule assembly. Podophyllotoxin and its derivatives are potent cytotoxic agents that inhibit cell mitosis and deoxyribonucleic acid dna synthesis in a manner similar to that of colchicine.
It acts by preventing viral wart cells from dividing and multiplying. Asymmetric synthesis of podophyllotoxin is achieved through tandem conjugate addition of s benzyl phenyl sulfoxide to but2en4olide. The american mayapple and its potential for podophyllotoxin. Order warticon warticon podophyllotoxin genital warts. The solution is prescribed to treat genital warts that appear on the outside of the body.
The first catalytic enantioselective total synthesis of podophyllotoxin is accomplished by a challenging organocatalytic crossaldol heck cyclization and distal stereocontrolled transfer. The key step in each of these syntheses is a spectacular intramolecular alkene arylation. Synthesis of podophyllotoxin journal of the american chemical. Podophyllotoxin is an important and much sought after antimitotic natural lead compound, since it paved the way for three hemisynthetic derivatives of podophyllotoxin, e. Molecules free fulltext advances in the synthesis of lignan. Podphyllotoxin is the most active cytotoxic natural product.
Leaves harvested in january and april exhibited higher podophyllotoxin contents 1. Podophyllotoxin is a medicine available in a number of countries worldwide. For centuries, native american tribes used the plant and its root for its medicinal, as well. As described above hydroxyacids 17a and 17b were obtained when performing the condensation on the trunethylsilyl ester 16. Synthesis of podophyllotoxin journal of the american.
Intensification of the coculture process is required to further improve total podophyllotoxin accumulation on a volumetric basis. Apart from the first nontereoselective synthesis reported by gensler5, to date only two total synthesis of 1 have been disclosed6. Several podophyllotoxin preparations are on the market for dermatological use to treat genital warts. Total synthesis ofpodophyllotoxin and epipo podophyllotoxin.
Asymmetric total synthesis of podophyllotoxin journal. Podophyllotoxin of 98% optical purity has been synthesized in eight steps and in 15% overall yield. Asymmetric total synthesis of podophyllotoxin rsc publishing. Department of chemistry, 630 natural sciences complex, the state university of new york at buffalo, buffalo, ny 14260, usa. The 1,2cis2,3trans configuration of ring c in the azapodophyllotoxin structure has been shown to be crucial for the compounds antitumor activity. Peng and coworkers reported the total synthesis of. C h bond arylation in the synthesis of aryltetralin lignans. Cupressaceae have been reported to contain podophyllotoxin, a pharmaceutical compound used to manufacture drugs for treatment of cancer, rheumatoid arthritis, genital warts, psoriasis, and multiple sclerosis.
Asymmetric total synthesis of podophyllotoxin journal of the. Podophyllotoxin 1 and epipodophyllotoxin 2 are two naturally occuring lignans3 with potent antimitotic activity4. A concise stereocontrolled formal total synthesis of. Metabolic engineering aimed at constructing the pathway in another host cell is very appealing, but for that. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the watersoluble prodrug, etoposide phosphate. Synthetic and application perspectives of azapodophyllotoxins. An account of our previously disclosed total synthesis of the aryltetralin lignan natural product podophyllotoxin, a building block used in the. Leaves of eastern red cedar juniperus virginiana l. It contains the active ingredient podophyllotoxin which prevents cell growth and kills the virus that causes the warts to appear. Since the total synthesis of podophyllotoxin is an expensive process, availability of the compound from natural renewable resources is an important issue for pharmaceutical companies that. To begin with, the compounds from higher plants include berbamine, butulinic acid, camptothecin, cucurbitacin, ellipticine, flavopiridol, homoharringtonine, silvestrol, berberine, daphnoretin and podophyllotoxin.
Warticon podophyllotoxin warticon is a medicine that is used to treat genital warts and is intended for external use only. Condyline topical solution containing the active ingredient podophyllotoxin belongs to a class of medications called antimitotics. Started in 1995, this collection now contains 6769 interlinked topic pages divided into a tree of 31 specialty books and 732 chapters. The key step, dielsalder addition of the quinonoid pyrone. Podophyllotoxin ppt, also known as podofilox, is a medical cream that is used to treat genital warts and molluscum contagiosum. Podophyllotoxin definition of podophyllotoxin by medical. Total synthesis of podophyllotoxin and epipo synthesis of the desired tetralin 30c would involve treatment of isoner 17a with mesyi chloride and triethylanine or burgess reagent vide supra. For centuries, native american tribes used the plant and its root for its medicinal, as well as poisonous, properties.
Currently, the commercial source of podophyllotoxin is the rhizomes and roots of podophyllum emodi wall. The medication works by penetrating the tissue of warts and preventing them from dividing and multiplying. Podophyllotoxin 1 and its derivative etoposide 2, derived from natural sources, are in current clinical use. We offer high quality products and jit services with instant market intelligence in china, custom synthesis in our 3 production sites, famous principals as brenntag, univar,s inopec, grace, petrobras, dksh, formitex, evonik, merck, tci, sanofi, chemo with creditable reputation and business cooperation. Shreeshailkumar b hadimani, rajendra p tanpure, sujata v bhat. Podophyllotoxin i, a wellknown naturally occurring aryltetralin lignan isolated from the root of podophyllum hexandrum, possesses potent antiproliferative activity against several tumor cell lines and has also been used as specific antimicrotubule agent acting at the colchicine binding site of tubulin 15. Wong bristolmyers company pharmaceutical research and development division 5 research parkway wallingford, connecticut 06492 abstract.
Podophyllum hexandrum royle of family berberidaceae is an endangered medicinal plant. Catalytic enantioselective synthesis of podophyllotoxin. It is used as starting compound for the synthesis of anticancer drug etoposide and teniposide. Podophyllotoxin is probably the most prominent representative of lignan natural products. A list of us medications equivalent to podophyllotoxin is available on the website. Structures of ypodophyllotoxin 1 and its congeners and derivatives. Indications, dose, contraindications, sideeffects, interactions, cautions, warnings and other safety information for podophyllotoxin. It is used for the treatment of hpv infections with external warts as well as molluscum contagisum infections. Total synthesis of podophyllotoxin and select analog designs via c.
There was no obvious pattern or trend in the data due to sampling date. Here in, we report a new method for the synthesis of the reported derivatives 4a, 4b, 5a, 5b. Synthesis although the natural podophyllin resin was used in folk medicine, it was not until its antitumor activity was con. Most of these triazole derivatives have good anticancer activity. Ppt cream is highly effective with minimal side effects, which are typically limited to itching, irritation, and redness. Podophyllotoxin content of leaves of immature, mature male, and mature female plants. Professor taber has more than 170 publications in the organic chemistry field, and has authored eight book chapters and three books. A straightforward approach to podophyllotoxin was developed using silyl enol ether 5. Synthesis of podophyllotoxin organic chemistry portal. Under the trade name condylox, a topical gel, it is used on the skin to treat external genital warts, caused by some types of the human papillomavirus hpv.
Podophyllotoxin abbreviated as ppt, otherwise known as podofilox, is a nonalkaloid toxin lignan extracted from the roots and rhizomes of podophyllum species. Synthesis of new tetralone intermediates for podophyllotoxin. Total synthesis highlights organic chemistry portal. Currently, the commercial source of podophyllotoxin is the rhizomes and roots of. Synthesis of podophyllotoxin cas no, with other names as 5r,5ar,8ar,9r9hydroxy53,4,5trimethoxyphenyl5,8,8a,9tetrahydrofuro3,4. Since the total synthesis of podophyllotoxin is an expensive process, availability of the compound from natural renewable resources is an important issue for pharmaceutical companies that manufacture these drugs. The overexploitation of this endangered plant has led to the search for alternative sources. Identification of the substancemixture and of the companyundertaking product name. Podophyllotoxin drug bnf content published by nice. The availability and stability of coniferin in the medium are the most likely factors limiting podophyllotoxin synthesis in coculture. H bonds represents one of the most remarkable reactions in modern organic chemistry. Sigmaaldrich offers a number of podophyllotoxin products. Apr 10, 2006 professor taber has more than 170 publications in the organic chemistry field, and has authored eight book chapters and three books. His research interests include the stereoselective synthesis of natural products, new methods in synthetic organic chemistry, and computational organometallic chemistry in organic synthesis.
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