- Total synthesis of podophyllotoxin and select analog designs via C–H activation
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An account of our previously disclosed total synthesis of the aryltetralin lignan natural product podophyllotoxin, a building block used in the synthesis of the FDA-approved anticancer drug etoposide, is disclosed. A C–H activation disconnection was viewed as being amenable to the preparation of E-ring modified analogs but proved challenging to execute. Various insights into palladium-catalyzed C–H arylation reactions on complex scaffolds are reported ultimately leading to the implementation of this strategy and the synthesis of compounds inaccessible by semisynthetic means.
- Ting, Chi P.,Tschanen, Esther,Jang, Esther,Maimone, Thomas J.
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- Chemoenzymatic Total Synthesis of Deoxy-, epi-, and Podophyllotoxin and a Biocatalytic Kinetic Resolution of Dibenzylbutyrolactones
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Podophyllotoxin is probably the most prominent representative of lignan natural products. Deoxy-, epi-, and podophyllotoxin, which are all precursors to frequently used chemotherapeutic agents, were prepared by a stereodivergent biotransformation and a biocatalytic kinetic resolution of the corresponding dibenzylbutyrolactones with the same 2-oxoglutarate-dependent dioxygenase. The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, “natural” structure and thus transforms various non-natural derivatives. Depending on the substitution pattern, the enzyme performs an oxidative C?C bond formation by C?H activation or hydroxylation at the benzylic position prone to ring closure.
- Lazzarotto, Mattia,Hammerer, Lucas,Hetmann, Michael,Borg, Annika,Schmermund, Luca,Steiner, Lorenz,Hartmann, Peter,Belaj, Ferdinand,Kroutil, Wolfgang,Gruber, Karl,Fuchs, Michael
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p. 8226 - 8230
(2019/05/21)
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- Stereoselective synthesis of 4β-acyloxypodophyllotoxin derivatives as insecticidal agents
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As our ongoing work on research of natural-product-based insecticidal agents, some 4α/β-acyloxypodophyllotoxin derivatives were synthesized, and were evaluated against the pre-third-instar larvae of B. mori, A. dissimilis and M. separate in vivo at the co
- Che, Zhi-Ping,Tian, Yue-E,Liu, Sheng-Ming,Jiang, Jia,Hu, Mei,Chen, Gen-Qiang
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p. 1028 - 1041
(2018/07/15)
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- Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis
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A nickel-catalyzed reductive cascade approach to the efficient construction of diastereodivergent cores embedded in podophyllum lignans is developed for the first time. Their gram-scale access paved the way for unified syntheses of naturally occurring podophyllotoxin and other members.
- Xiao, Jian,Cong, Xiao-Wei,Yang, Gui-Zhen,Wang, Ya-Wen,Peng, Yu
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p. 1651 - 1654
(2018/03/23)
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- Preparation method of etoposide, teniposide and analogs of etoposide and teniposide
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The invention discloses a preparation method of etoposide, teniposide and analogs of etoposide and teniposide. The preparation method includes the following steps of 1, selective protection of 4'domethylpodophyllotoxin4'hydroxy; 2, introduction of 4 hydroxy hydroxyl; 3, removal of a protecting group. The method is mild in reaction condition and environmentally friendly, and the yield and purity of the products are high.
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Paragraph 0041; 0042; 0043
(2017/01/02)
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- Synthesis and Biological evaluation of novel 4β-[(5-substituted)-1,2,3,4-tetrazolyl] podophyllotoxins as anticancer compounds
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A series of novel 4β-[(5-substituted)-1,2,3,4-tetrazolyl] podophyllotoxin derivatives were synthesized by employing azide-nitrile click chemistry approach. All the derivatives were evaluated for their cytotoxicity against a panel of four human cancer cell lines and their IC50 values were found to be in the range of 2.4-29.06 μM. The cytotoxicity exhibited by the majority of test compounds were found to comparable and often more effective than doxorubicin and all compounds exhibited higher cytotoxicity on A-549 cell lines. Cell cycle analysis showed that the novel 4β-[(5-substituted)-1,2,3,4-tetrazolyl] podophyllotoxins resulted in cell cycle arrest at G2/M phase and were also found to be the potent inhibitors of tubulin polymerization in vitro.
- Hyder, Irfan,Yedlapudi, Deepthi,Kalivendi, Shasi V.,Khazir, Jabeena,Ismail, Tabasum,Nalla, Naresh,Miryala, Sreekanth,Sampath Kumar, Halmuthur M.
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supporting information
p. 2860 - 2863
(2015/06/08)
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- One-pot synthesis of podophyllotoxin-thiourea congeners by employing NH2SO3H/NaI: Anticancer activity, DNA topoisomerase-II inhibition, and apoptosis inducing agents
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A facile one-pot method for the synthesis of novel podophyllotoxin-thiourea congeners has been developed by using NH2SO3H/NaI system. Interestingly, 4β-azido podophyllotoxin reduction with concomitant aryl isothiocyanates coupling un
- Shankaraiah, Nagula,Kumar, Niggula Praveen,Amula, Suresh Babu,Nekkanti, Shalini,Jeengar, Manish Kumar,Naidu,Reddy, T. Srinivasa,Kamal, Ahmed
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supporting information
p. 4239 - 4244
(2015/11/03)
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- Differential Targeting of Human Topoisomerase II Isoforms with Small Molecules
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(Chemical Equation Presented). The TOP2 poison etoposide has been implicated in the generation of secondary malignancies during cancer treatment. Structural similarities between TOP2 isoforms challenge the rational design of isoform-specific poisons to further delineate these processes. Herein, we describe the synthesis and biological evaluation of a focused library of etoposide analogues, with the identification of two novel small molecules exhibiting TOP2B-dependent toxicity. Our findings pave the way toward studying isoform-specific cellular processes by means of small molecule intervention.
- Mariani, Angelica,Bartoli, Alexandra,Atwal, Mandeep,Lee, Ka C.,Austin, Caroline A.,Rodriguez, Rapha?l
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supporting information
p. 4851 - 4856
(2015/06/25)
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- Synthesis and biological evaluation of 4β-benzoxazolepodophyllotoxin hybrids as DNA topoisomerase-II targeting anticancer agents
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A series of new 4β-benzoxazolepodophyllotoxin compounds (9a-j) were prepared and screened for cytotoxicity against four human tumour cell lines (HeLa, DU-145, A-159 and MCF-7). Among these compounds, 9a, 9c, 9f and 9i have shown more potent anticancer activity than etoposide with considerable IC50 values. Apoptosis evaluation studies were performed using the Hoechst-33258 staining method and it was found specially that the best active compound 9i shows clear nuclear damage compared to etoposide. Molecular docking studies were also carried out to recognize the interactions against DNA topoisomerase-II and it was found that the energy calculations were in good agreement with the observed IC50 value.
- Paidakula, Suresh,Kankala, Shravankumar,Kankala, Ranjith Kumar,Juluru, Bhasker,Jonnalagadda, Sreekantha B.,Lee, Chia-Hung,Vadde, Ravinder,Vasam, Chandra Sekhar
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p. 97314 - 97319
(2015/11/28)
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- Ci-H bond arylation in the synthesis of aryltetralin lignans: A short total synthesis of podophyllotoxin
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A short total synthesis of podophyllotoxin, the prototypical aryltetralin lignan natural product, is reported. Key to the success of this synthetic pathway is a Pd-catalyzed C(sp3)-H arylation reaction enabled by a conformational biasing element to promote C-C reductive elimination over an alternative Ci-N bond-forming pathway. This strategy allows for access to the natural product in five steps from commercially available bromopiperonal, and sheds light on subtle conformational effects governing reductive elimination pathways from high-valent palladium centers. Testing a new tactic: In a concise synthesis of podophyllotoxin with a crucial palladium-catalyzed arylation step, subtle conformational effects govern reductive elimination pathways from the high-valent palladium center. This route to aryltetralin lignan derivatives may be of interest in drug discovery.
- Ting, Chi P.,Maimone, Thomas J.
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p. 3115 - 3119
(2014/04/03)
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- Insight into dihalogenation of E-ring of podophyllotoxins, and their acyloxyation derivatives at the C4 position as insecticidal agents
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Unexpected sequential E-ring dihalogenation of podophyllotoxin analogues is reported. It demonstrated that a chlorine/bromine atom was prior introduced at the C2′ position of podophyllotoxin, and the corresponding free rotation of E-ring around the C1-C1′
- Che, Zhiping,Yu, Xiang,Fan, Lingling,Xu, Hui
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supporting information
p. 5592 - 5598
(2013/10/01)
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- Synthesis of 4β-carbamoyl epipodophyllotoxins as potential antitumour agents
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A series of new 4β-carbamoyl epipodophyllotoxin analogues have been synthesized and evaluated for their anticancer activity against eleven cancer cell lines including Zr-75-1, MCF7, KB, Gurav, DWD, Colo 205, A-549, Hop62, PC3, SiHa and A-2780. Most of the
- Kamal, Ahmed,Ashwini Kumar,Suresh, Paidakula,Juvekar, Aarti,Zingde, Surekha
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experimental part
p. 2975 - 2979
(2011/06/19)
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- Natural products-based insecticidal agents 6. Design, semisynthesis, and insecticidal activity of novel monomethyl phthalate derivatives of podophyllotoxin against Mythimna separata Walker in vivo
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To discover the more potent analogs, 12 novel monomethyl phthalate derivatives of podophyllotoxin were synthesized and preliminarily tested against the pre-third-instar larvae of Mythimna separata Walker in vivo at the concentration of 1 mg/mL. Compounds 8e-i showed the higher insecticidal activity than podophyllotoxin. Especially 8g exhibited the most potent insecticidal activity compared with toosendanin, a commercially available insecticide derived from Melia azedarach. The structure-activity relationships demonstrated that trans-lactone, 4β-substitution, 2β-chlorine substitution, and 4′-methoxy group were the important structural properties of podophyllotoxins for good insecticidal activity.
- Xu, Hui,He, Xiao-Qiang
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scheme or table
p. 4503 - 4506
(2010/11/24)
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- NOVEL GEM-DIFLUORINATED C-GLYCOSIDE COMPOUNDS DERIVED FROM PODOPHYLLOTOXIN, THEIR PREPARATION AND THEIR APPLICATIONS
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The invention relates to a gem-difluoride glycoconjugated compound with formula (I): where R represents II or a benzyl, acetyl, benzoyl alkyl group, R1 and R2 may be identical or different and represent H or an alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl, tertiobutyldiphenylsilyl protective group or an acetal group of the CR′R′ type, where R′ and R′ may be identical or different and represent H or an alkyl, aryl, benzyl or thiophene group, R3 represents H or an alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl or tertiobutyldiphenylsilyl protective group, R4 represents OR″, NGR′GR′, N3, or a phthalimide, where R″ represents H or an alkyl, benzyl, benzoyl, acetyl, pivaloyl, trialkylsilyl or tertiobutyldiphenylsilyl protective group, GR′ and GR′ may be identical or different and represent II or an alkyl, benzyl, benzoyl, acetyl, alkyloxycarbonyl, allyloxycarbonyl or benzyloxycarbonyl group, R5 represents a free or protected hydroxyl group or a halogen, R6 represents H or an alkyl, acetyl, benzyl, PO3H or PO3Na group. It is applicable to the preparation of compounds that can be used particularly for the treatment of cancer.
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Page/Page column 5-6
(2009/12/28)
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- Silenes in organic synthesis: A concise synthesis of (±)-epi- picropodophyllin
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A concise, seven step synthesis of the aryl tetralin lignan lactone epi-picropodophyllin from piperonal is described. The key steps are a silene diene Diels-Alder reaction and the Hosomi-Sakurai reaction of the resultant silacyclohexene. The Royal Society
- Pullin, Robert D. C.,Sellars, Jonathan D.,Steel, Patrick G.
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p. 3201 - 3206
(2008/04/01)
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- A concise stereocontrolled formal total synthesis of (+/-)-podophyllotoxin using sulfoxide chemistry.
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A short stereoselective formal total synthesis of (+/-)-podophyllotoxin has been carried out from a sulfoxide, using a one-pot tandem conjugate addition/aldol/electrophilic aromatic substitution reaction to form a tetralin, which was converted into picrop
- Casey, Mike,Keaveney, Claire M
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p. 184 - 185
(2007/10/03)
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- Efficient enantioselective total synthesis of (-)-epipodophyllotoxin
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In only twelve steps the total synthesis of (-)-epipodophyllotoxin (2) has been completed starting from commercially available piperonal (1). The first stereo-center was formed under auxilary control, while the following epoxidation and radical cyclization proceeded with outstanding diastereoselectivity, which enabled the target molecule to be isolated in an overall yield of 30% and with 97% ee.
- Engelhardt, Ulrike,Sarkar, Arunkanti,Linker, Torsten
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p. 2487 - 2489
(2007/10/03)
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- A one-pot, efficient and facile synthesis of 4β -arylaminopodophyllotoxins: Synthesis of NPF and GL-331 as DNA topoisomerase II inhibitors
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A series of 4β-arylamino-4′-O-demethylepipodophyllotoxins and 4β-arylaminopodophyllotoxins have been synthesized with significant stereoselectivity and improved yields by employing the BF3· OEt2/NaI reagent system. Compounds NPF, GL-331 and other DNA topoisomerase II inhibitors have been prepared in good to excellent yields by employing this methodology.
- Kamal, Ahmed,Kumar, B. Ashwini,Arifuddin
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p. 8457 - 8459
(2007/10/03)
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- Facile and efficient one-pot synthesis of 4β-arylamino-podophyllotoxins: Synthesis of DNA topoisomerase II inhibitors (NPF and W-68)
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A series of 4β-arylamino-4'-O-demethylepipodophyllotoxins and 4β-arylaminoepipodophyllotoxins have been synthesized with significant stereoselectivity and improved yields by employing the methanesulphonic acid/sodium iodide reagent system. Compounds NPF, W-68 and other DNA topoisomerase II inhibitors are prepared in good to excellent yields by this method and these are active or more active than etoposide in their inhibition of the human DNA topoisomerase II. (C) 2000 Elsevier Science Ltd.
- Kamal, Ahmed,Laxman,Ramesh
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p. 2059 - 2062
(2007/10/03)
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- A one-pot, efficient synthesis of the potent cytotoxic podophyllotoxin derivative NPF
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One-pot syntheses of 4'-demethylepipodophyllotoxin 7 and NPF 2 (4'-O-demethyl-4β-(4'-fluoroanilino )-4-deoxypodaphyllotoxin) are described from podophyllotoxin 3 via a protocol using trimethylsilyl iodide in 72% and 52% overall yields, respectively.
- Daley, Laurent,Meresse, Philippe,Bertounesque, Emmanuel,Monneret, Claude
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p. 2673 - 2676
(2007/10/03)
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- Azepines by Photochemical Ring Enlargement of 9-Azidopodophyllotoxin- and 9-Azido-9'-demethylepipodophyllotoxin Derivatives
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The azepines 5a-5c were obtained by photochemical nitrene rearrangement of the azides 1e/1f and 4b/4c in cyclohexene, but not in other solvents.They are ring expansion products of podophyllotoxin (1a) and resemble steganacin (9), but show only low biological activity.The triazenes 7a/8a and the aziridine 8b are also less active than 1a. - Keywords: Podophyllotoxin / Podophyllotoxin azides / Nitrene rearrangement
- Laatsch, Hartmut,Ernst, Bernd Peter,Hoffmann, Dieter
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p. 1773 - 1778
(2007/10/03)
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- A Mild Method for Selective Cleavage of Tetrahydropyranyl Ethers in the Presence of Other Acid-Labile Functionalities
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A mild method for selective cleavage of tetrahydropyranyl ethers in the presence of other acid sensitive functionalities such as acetonides, methoxymethyl ethers, methylenedioxy ethers, mesitylaldehyde acetals and t-butyldimethylsilyl ethers using Lewis acid-thiol system is described.
- Nambiar, Krishnan P.,Mitra, Abhijit
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p. 3033 - 3036
(2007/10/02)
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- Synthesis of (+/-)-4-Deoxypodophyllotoxin, (+/-)-Podophyllotoxin and (+/-)-Epipodophyllotoxin
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6,7-Methylenedioxy-1-(3',4',5'-trimethoxyphenyl)-2-benzopyran-3-one 1 and dimethyl fumarate in acetonitrile give mostly the C-2 exo-CO2Me adduct 4 which is transformed in four steps into epipodophyllotoxin 10a.Attempted addition of dimethyl maleate to 1 p
- Jones David W.,Thompson, Adrian M.
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p. 2541 - 2548
(2007/10/02)
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- Synthesis of Podophyllum Lignans via an Isolable o-Quinonoid Pyrone
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The 2-benzopyran-3-one 10 is a stable, isolable and useful Diels-Alder diene; its methyl 4-benzoyloxycrotonate adduct 23 formed regioselectively and stereoselectively in acetonitrile is reduced with H2/Pd to give 31 with inversion of C-1 stereochemistry.T
- Jones, David W.,Thompson, Adrian M.
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p. 2533 - 2540
(2007/10/02)
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- Antitumor agents. I. DNA topoisomerase II inhibitory activity and the structural relationship of podophyllotoxin derivatives as antitumor agents
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Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and a
- Terada,Fujimoto,Nomura,Yamashita,Kobunai,Takeda,Wierzba,Yamada,Yamaguchi
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p. 2720 - 2727
(2007/10/02)
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- Enantioselective Total Synthesis of (-)-Epipodophyllotoxin and (-)-Podophyllotoxin
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An enantioselective total synthesis of (-)-epipodophyllotoxin (2) and hence of (-)-podophyllotoxin (1) is described, involving as key steps a conjugate addition on butenolide 13 as the chiral template, a stereoselective aldol condensation on 11a and a ste
- Speybroeck, R. Van,Guo, H.,Eycken, J. Van der,Vandewalle, M.
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p. 4675 - 4682
(2007/10/02)
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- Comprehensive Synthetic Route to Eight Diastereomeric Podophyllum Lignans
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An oxabicyclo compound, 9, prepared in 47percent yield through an isobenzofuran intermediate was converted with excellent regio- and stereocontrol to eight (+/-)-lignan lactones of the podophyllotoxin series.One of the eight, epiisopicropodophyllin, 36, t
- Forsey, Steven P.,Rajapaksa, Dayananda,Taylor, Nicholas J.,Rodrigo, Russell
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p. 4280 - 4290
(2007/10/02)
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- ACETYLATED LIGANDS FROM JUNIPERUS SABINA
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Key Word Index--Juniperus sabina; Cupressaceae; lignans; acetyl-epipodophyllotoxin; acetyl-epipicropodophyllotoxin.Abstract--Two new natural products, the acetates of epipodophyllotoxin and epipicropodophyllotoxin, were isolated from the lignan fraction of a n-hexane extract of the leaves of Juniperus sabina, along with deoxypodophyllotoxin, deoxipicropodophyllotoxin, (-)-deoxypodorhizon, β-peltatin A methyl ether and picropodophyllotoxin.
- Feliciano, Arturo San,Corral, Jose M. Miguel Del,Gordaliza, Marina,Castro, M. Angeles
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p. 659 - 660
(2007/10/02)
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- A SHORT VERSATILE SYNTHESIS OF ARYLTETRALIN LIGNANS INCLUDING DEOXYISOPODOPHYLLOTOXIN AND EPI-ISOPODOPHYLLOTOXIN
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Cyclisation of tandem conjugate addition products (10), (15), and (20), prepared by reaction of anions derived from benzyl phenyl and benzyl t-butyl sulphides with but-2-en-4-olide, affords a series of aryltetralin lignans belonging to either the 'normal' or the 'retro' lactone series.Desulphurisation of compound (15) followed by cyclisation, or desulphurisation of the cyclised product (22b), affords deoxyisopodophyllotoxin (5), while treatment of compound (22b) with mercury(II) trifluoroacetate yields epi-isopodophyllotoxin (6).
- Pelter, Andrew,Ward, Robert S.,Pritchard, Martyn C.,Kay, I. Trevor
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p. 1615 - 1624
(2007/10/02)
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- Synthesis of Podophyllum Lignans via an Isolable o-Quinonoid Pyrone
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The 2-benzopyran-3-one (7) is a stable, isolable, and useful Diels-Alder diene; its adduct (10) formed with dimethyl fumarate is transformed in three steps into methyl epipodophyllate (14) which gives epipodophyllotoxin (2) (81percent) by direct lactonisation (ZnCl2-tetrahydrofuran-4 Angstroem molecular sieves).
- Jones, David W.,Thompson, Adrian M.
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p. 1797 - 1798
(2007/10/02)
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- TOTAL SYNTHESIS OF (+/-)-PODOPHYLLOTOXIN AND (+/-)-EPIPODOPHYLLOTOXIN
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A novel approach to (+/-)-epipodophyllotoxin (2c) and hence also to (+/-)-podophyllotoxin (1c) is described, involving as a key-step the stereoselective ring closure of the TMS-ester derived from 17a to the tetralin derivative 30c with mesyl chloride.
- Eyken, J. Van der,Clercq, P. de,Vandewalle, M.
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p. 4297 - 4308
(2007/10/02)
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- Antitumor Agents. 78. Inhibition of Human DNA Topoisomerase II by Podophyllotoxin and α-Peltatin Analogues
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It has been reported that the action of etoposide (VP-16) (14) as an antitumor agent is mediated through its interaction with DNA topoisomerase II which results in DNA breakage inside the cell.In order to understand the mechanism of action as well as structure-activity relationships of 14, several novel, synthetic and some naturally occurring analogues related to podophyllotoxin were examined for inhibition of the DNA topoisomerase II activity.Compound 2 exhibited enhanced activity and compound 5 slightly diminished activity relative to 14.A 4β-substituted ether at the C ring and O-demethylation at the E ring appear to enhance activity.
- Thurston, Lee S.,Irie, Hiroshi,Tani, Shohei,Han, Fu-Sheng,Liu, Zong-Chao,et al.
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p. 1547 - 1550
(2007/10/02)
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- Studies on the Constituents of the Seeds of Hernandia ovigera L. V. Syntheses of Epipodophyllotoxin and Podophyllotoxin from Desoxypodophyllotoxin
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Epipodophyllotoxin (EPT) and podophyllotoxin (PT) were prepared from desoxypodophyllotoxin (DPT), obtained from the seeds of Hernandia ovigera L. (Hernandiaceae).EPT was obtained together with dehydrodesoxypodophyllotoxin (I) by a radical bromination of D
- Yamaguchi, Hideo,Arimoto, Masao,Nakajima, Syunji,Tanoguchi, Mariko,Fukada, Yoshinari
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p. 2056 - 2060
(2007/10/02)
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- TOTAL SYNTHESIS OF (+/-)-PODOPHYLLOTOXIN AND (+/-)-EPIPODOPHYLLOTOXIN.
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A novel approach to (+/-)-epipodophyllotoxin (2) and hence also (+/-)-podophyllotoxin (1) is described, involving as a key-step the stereoselective ring closure of the TMS-ester derived from 14a to the tetralin derivative 15 with mesyl chloride.
- Eycken, J. Van der,Clercq, P. De,Vandewalle, M.
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p. 3871 - 3874
(2007/10/02)
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- SYNTHESIS OF DEOXYISOPODOPHYLLOTOXIN AND EPIISOPODOPHYLLOTOXIN.
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Cyclisation of the tandem conjugate addition products 1-3 by displacement of either the OH or SPh group provides a short efficient synthesis of lignan lactones including compounds of the clinically important podophyllotoxin series.
- Pelter, Andrew,Ward, Robert S.,Pritchard, Martyn C.,Kay, I. Trevor
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p. 6377 - 6380
(2007/10/02)
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