- Synthesis and Biological Activity of Ferrocenyl and Ruthenocenyl Analogues of Etoposide: Discovery of a Novel Dual Inhibitor of Topoisomerase II Activity and Tubulin Polymerization
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Two series of the ferrocenyl and ruthenocenyl analogues of etoposide bearing 1,2,3-triazolyl or aminoalkyl linker were synthesized and evaluated for their cytotoxic properties, influence on the cell cycle, ability to induce tubulin polymerization, and inhibition of topoisomerase II activity. We found that the replacement of the etoposide carbohydrate moiety with a metallocenyl group led to organometallic conjugates exhibiting differentiated antiproliferative activity. Biological studies demonstrated that two ferrocenylalkylamino conjugates were notably more active than etoposide, with submicromolar or low-micromolar IC50 values towards SW620, etoposide-resistant SW620E, and methotrexate-resistant SW620M cancer cell lines. Moreover, the simplest ferrocenylmethylamino conjugate exerted dual inhibitory action against tubulin polymerization and topoisomerase II activity while other studied compounds affected only topoisomerase II activity.
- Chrab?szcz, Karolina,B?au?, Andrzej,Grucha?a, Martyna,Wachulec, Marcin,Rychlik, B?a?ej,Pla?uk, Damian
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p. 6254 - 6262
(2021/03/09)
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- Preparation method for total synthesis of 4'-demethylepipodophyllotoxin
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The invention discloses a preparation method for total synthesis of 4'-demethylepipodophyllotoxin (also named as epipodophyllotoxin). The preparation method comprises the following steps: (1) syringaldehyde (compound 1) used as an initial material and benzyl methoxyacyl used as a protective group are in favor of a chemical reaction of finally removing the protective group to obtain a target compound; (2) a chiral target object is produced by adopting an asymmetric hydrogenation reduction reaction in which a chiral ligand (s-BINAN Ru (II)) participates; and (3) a reaction of hydrogenating and deprotecting groups is also carried out in parallel while chiral catalytic hydrogenation is carried out. The reaction steps and treatment are saved, the route selection is targeted to the target compound, the production cost is low, and the environment is friendly.
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Paragraph 0023; 0041; 0055; 0056
(2020/06/02)
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- Biotin-podophyllotoxin derivative and its pharmaceutical compositions and methods for their preparation and use
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The invention provides a biotin-podophyllotoxin esterified derivative represented as the general formula (I), pharmaceutical composition taking compounds as active ingredients, as well as applications of the biotin-podophyllotoxin esterified derivative in preparing antitumor drugs and inhibitors. Activity screening proves that the biotin-podophyllotoxin esterified derivative represented as the general formula (I) has better antitumor activity. Meanwhile, a preparation method of the compounds is provided and comprises the following steps: podophyllotoxin is taken as a lead compound, structures of hydroxyl at the 4 site and methoxyl at the 4' site are modified, and a series of compounds are synthesized through connection of different chains between biotin and podophyllotoxin. According to the invention, biotin which is necessary for cell growth is used for structure modification on podophyllotoxin, cancer cell targeting selectivity of a modifier is improved, selective distribution toward cancer cells is realized, and better treatment effect can be achieved. Meanwhile, biotin is soluble in water, and the water solubility problem of drugs can be solved by introducing biotin into podophyllotoxin molecules.
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Paragraph 0040-0041
(2016/10/10)
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- Design, synthesis and biological evaluation of novel podophyllotoxin derivatives bearing 4β-disulfide/trisulfide bond as cytotoxic agents
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A novel series of C-4β-disulfide/trisulfide-containing podophyllotoxin derivatives were designed, synthesized, and biologically evaluated for their cytotoxic activities against human cancer cell lines, including KB (Mouth Epidermal Carcinoma Cells) and KB/VCR (Vincristine-resistant Mouth Epidermal Carcinoma Cells). Most of these compounds exhibited promising moderate to good cytotoxic activities. In particular, some of them displayed even superior activities to that of etoposide, especially for KB/VCR cell lines, indicating that introduction of the disulfide/trisulfide moiety would be beneficial for overcoming the multi-drug resistant limitation of etoposide. Moreover, the metabolic evaluation of the most promising compound was further performed to reveal that disulfide bond can be stable in human plasma over 8 hours, indicating good potential of these compounds for in vivo anti-cancer activities.
- Zhu, Shi-Jun,Ying, Hua-Zhou,Wu, Yan,Qiu, Ni,Liu, Tao,Yang, Bo,Dong, Xiao-Wu,Hu, Yong-Zhou
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p. 103172 - 103183
(2015/12/23)
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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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- 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 evaluation of the apoptosis inducing and CT DNA interaction properties of a series of 4β-carbamoyl 4′-O- demethylepipodophyllotoxins
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A series of carbamate derivatives of 4′-demethylepipodophyllotoxin have been synthesized, and their cytotoxicities against several human cancer cell lines, including HeLa, A549, HCT-8, and HL-60 cells, evaluated. Some of these compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. 4β-4′-Demethylepipodophyllotoxin 1-(4-nitrophenyl) piperazinyl carbamate (19) was found to be the most potent compound of those synthesized in the current study, and induced cell cycle arrest in the G2/M phase in HeLa cells, which was accompanied by apoptosis. Furthermore, this compound activated the expression of Bax, p53 and caspase-3 in HeLa cells, leading to changes in the conformation of calf thymus DNA from the B-form to a more compact C-form.
- Sang, Chun-Yan,Liu, Jian-Fei,Qin, Wen-Wen,Zhao, Jie,Hui, Lin,Jin, Yong-Xin,Chen, Shi-Wu
-
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- Synthesis and cytotoxic activity on human cancer cells of carbamate derivatives of 4β-(1,2,3-triazol-1-yl)podophyllotoxin
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Carbamate derivatives of 4β-(1,2,3-triazol-1-yl)podophyllotoxin were synthesized by means of click chemistry, and their cytotoxicities against human cancer cell lines HL-60, A-549, HeLa, and HCT-8 were evaluated. Some compounds were more potent than the anticancer drug etoposide. 4′-O-Demethyl- 4β-[(4-hydroxymethyl)-1,2,3-triazol-1-yl]-4-deoxypodophyllotoxin cyclopentyl carbamate, the most potent compound, induced cell cycle arrest in the G2/M phase accompanied by apoptosis in A-549 cells. Furthermore, this compound inhibited the formation of microtubules in A-549 cells and caused the inhibition of DNA topoisomerase-II.
- Liu, Jian-Fei,Sang, Chun-Yan,Xu, Xiao-Hui,Zhang, Lin-Lin,Yang, Xuan,Hui, Lin,Zhang, Jin-Bang,Chen, Shi-Wu
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p. 621 - 628
(2013/07/27)
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- Practical demethylation of podophyllotoxin and efficient preparation of 4-amino-4-deoxy-4′-demethylepipodophyllotoxin
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(Chemical Equation Presented) 4′-Demethylepipodophyllotoxin (4′-DMEP) was readily available through demethylation of podophyllotoxin using methionine in methanesulfonic acid in the presence of TFA (or acetone/water). Thus, 4-amino-4-deoxy-4′-demethylepipodophyllotoxin was obtained in three steps in excellent yield by a Ritter reaction on 4′-DMEP, followed by treatment with thiourea in AcOH. Copyright Institut de Recherche Pierre Fabre.
- Guminski, Yves,Grousseaud, Martial,Cugnasse, Sandrine,Imbert, Thierry
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experimental part
p. 2780 - 2789
(2012/07/30)
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- Synthesis and evaluation of aroylthiourea derivatives of 4-β-amino-4'-O-demethyl-4-desoxypodophyllotoxin as novel topoisomerase II inhibitors
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A novel series of aroylthiourea derivatives of 4-β-amino-4′-O- demethyl-4-desoxy- podophyllotoxin were synthesized. Their cytotoxicities against three cancer cell lines were investigated by MTT assay. The kDNA decatenation assay indicated that compounds 5a, 5f, 5h and 5l inhibited topoisomerase II-mediated kDNA decatenation. DNA flow cytometric analysis revealed that compound 5a induced cell cycle arrest at G2/M phase in HCT-116 cell line.
- Zhao, Yu,Ge, Cun Wang,Wu, Zhong Hua,Wang, Cheng Niu,Fang, Jing Huai,Zhu, Li
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scheme or table
p. 901 - 906
(2011/04/19)
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- Synthesis and biological evaluation of derivatives of 4- deoxypodophyllotoxin as antitumor agents
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In an attempt to generate compounds with superior bioactivity and reduced toxicity, a series of derivatives of deoxypodophyllotoxin were synthesized by reacting 4′-demethyl-4-deoxypodophyllotoxin with substituted piperazines or their amino acid amides. The cytotoxic activity of these compounds against three human cancer cell lines was evaluated. We found that p- nitrophenylpiperazine substitution (Compound 8b) led to an increase in the potency of the compound. Compound 8b exhibited the most potent cytotoxicity against A-549, HeLa and SiHa cells (IC50 values were 0.102, 0.180 and 0.0195 μM, respectively). In addition, flow cytometric analysis showed that 8b induced cell cycle arrest in the G1 phase accompanied by apoptosis in A-549 cells.
- Jin, Yan,Liu, Jie,Huang, Wen-Ting,Chen, Shi-Wu,Hui, Ling
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scheme or table
p. 4056 - 4061
(2011/11/12)
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- Carbamates of 4′-demethyl-4-deoxypodophyllotoxin: Synthesis, cytotoxicity and cell cycle effects
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In an attempt to generate compounds with superior bioactivity and reduced toxicity, 12 carbamates of 4′-demethyl-4-deoxypodophyllotoxin, N-(1-oxyl-4′-demethyl- 4-deoxypodophyllic)-α-amino acids amides, were synthesized and evaluated for antiproliferative activity and cell cycle effects. These synthesized compounds proved to be more hydrophilic, as well as improved or comparable in vitro cytotoxicities against four cell lines (A-549, HeLa, SiHa, and HL-60) compared with either parent DPT or anti-cancer drug VP-16. Furthermore, flow cytometric analysis exhibited that N-(1-oxyl-4′- demethyl-4-deoxypodophyllic)-d-α-methine amide (15f) induced cell cycle arrest in the G2/M phase in A-549 cells.
- Chen, Shi-Wu,Gao, Yuan-Yu,Zhou, Ni-Ni,Liu, Jie,Huang, Wen-Ting,Hui, Ling,Jin, Yan,Jin, Yong-Xin
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supporting information; scheme or table
p. 7355 - 7358
(2012/02/04)
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- Design and synthesis of novel cytotoxic podophyllotoxin derivatives
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In order to investigate the effect of different C4 linkage moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4-N- and 4-C-substituted 4'-O-demethylepipodophyllotoxin derivatives were designed and synthesized. All the compounds were tested against A549 and MCF-7 tumor cells in vitro, and six compounds showed significant cytotoxicity. The most active compound 9f was superior to GL-331, and exhibited potent cytotoxicity with IC50 value at 10-7mol/L level.
- Xi, Wen Li,Cai, Qian,Tang, Yan Bo,Sun, Hua,Xiao, Zhi Yan
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scheme or table
p. 1153 - 1156
(2011/10/08)
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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.
- -
-
Page/Page column 5-6
(2009/12/28)
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- Synthesis and anti-HIV-1 activities of novel podophyllotoxin derivatives
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In order to explore the range of biological activities of the podophyllotoxin compound class, a novel series of derivatives of podophyllotoxin, which were conjugates containing stavudine and different structural podophyllotoxin analogues, were designed, synthesized, and evaluated for their anti-HIV-1 activities in vitro. Among these compounds, 19d and 19c showed the highest anti-HIV-1 activities with EC50 values of 0.17 and 0.29 μM and TI values of 466.9 and 354.5, respectively.
- Chen, Shi-Wu,Wang, Yun-Hua,Jin, Yan,Tian, Xuan,Zheng, Yong-Tang,Luo, Du-Qiang,Tu, Yong-Qiang
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p. 2091 - 2095
(2008/02/02)
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- Design, synthesis, and biological evaluation of novel pyridine acid esters of podophyllotoxin and esters of 4′-demethylepipodophyllotoxin
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Podophyllotoxin and related analogs present numerous challenges associated with optimal antitumor activity and severe unpredictable toxicity. In the course of our ongoing investigation of quantitative structure-activity relationships to find biorational antitumor drugs, two series of pyridine acid ester derivatives of podophyllotoxin and 4′-demethylepipodophyllotoxin have been prepared by reacting the corresponding pyridine acids with the hydroxyl group of podophyllotoxin and 4′-demethyl epipodophyllotoxin in the presence of dimethylaminopyridine (DMAP) and N,N-dicyclohexylcarbodiimde (DCC). The structures of the compounds were extensively characterized by using 1H-nuclear magnetic resonance, mass spectroscopy, infrared, and elemental analysis and evaluated for their in vitro cytotoxicity on two neoplastic cell lines (P-388 murine leukemia, A-549 human lung carcinoma) using a MTT-based assay, the results indicated significantly higher efficacy of these compounds in comparison with the prototypical inhibitor etoposide. On the basis of the preliminary biological testing results, it suggested that the cytotoxic activity of OCH3 at C-4′ is more potent than that of its demethylated analogs and the podophyllotoxin substitution at C-4 may be optimal for synthesizing more potent cytotoxic compounds.
- Liu, Ying-Qian,Yang, Liu,Tian, Xuan
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p. 319 - 330
(2008/12/21)
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- (POLY) AMINOACETAMIDE DERIVATIVES OF EPIPODOPHYLLOTOXIN THEIR PROCESS OF PREPARATION AND THEIR APPLICATIONS IN THERAPEUTICS AS ANTICANCER AGENTS
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The present invention relates to novel podophyllotoxin derivatives substituted in the 4-position by a substituted (poly)aminoalkylaminoacetamide chain, to their process of preparation and to their use as medicament as anticancer agents.
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Page/Page column 16
(2008/06/13)
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- Synthesis and biological study of a new series of 4′- demethylepipodophyllotoxin derivatives
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Etoposide (VP-16) is a potent human DNA topoisomerase II poison, derived from 4′-demethylepipodophyllotoxin, widely used in cancer chemotherapy. Continuous efforts have driven to synthesize new related compounds, presenting decreased toxic side effects, metabolic inactivation, drug resistance, and increased water solubility. Identified structure-activity relationships have pointed out the importance of the 4β-substitution and of the configuration of the D ring. Here we report the synthesis of two novel series of derivatives of 4′-demethylepipodophyllotoxin. The first bears a carbamate chain in the 4 position (13a-f), whereas, in the second series, in addition to this chain, the lactone ring has been modified by shifting the carbonyl from position 13 to position 11 (27a-f). Moreover, an analogue of TOP-53 having this lactone modification has also been prepared (32). From this study, structure-activity relationships were established. Compounds 13a and 27a displayed potent cytotoxic activity against the L1210 cell line (10 to 20-fold higher than VP-16) and proved to be strong topoisomerase II poisons more potent than VP-16. From preliminary in vivo investigation of both compounds against P388 leukemia and orthotopically grafted human A549 lung carcinoma, it appeared that 13a and 27a constitute promising leads for a new class of antitumor agents.
- Duca, Maria,Guianvarc'h, Dominique,Meresse, Philippe,Bertounesque, Emmanuel,Dauzonne, Daniel,Kraus-Berthier, Laurence,Thirot, Sylvie,Léonce, Stéphane,Pierré, Alain,Pfeiffer, Bruno,Renard, Pierre,Arimondo, Paola B.,Monneret, Claude
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p. 593 - 603
(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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- Synthesis of 4beta-amido and 4beta-sulphonamido analogues of podophyllotoxin as potential antitumour agents.
-
The new 4beta-amido analogues of podophyllotoxin or 4'-O-demethylepipodophyllotoxin have been prepared either by the coupling of 4beta-amino podophyllotoxin or 4beta-amino-4'-O-demethyl epipodophyllotoxin with the corresponding acids in presence of DCC in dichloromethane or by treating the appropriate acid chloride or sulphonyl chloride in presence of Et(3)N. These 4beta-amido and 4beta-sulphonamido derivatives of podophyllotoxin have been evaluated for their cytotoxicity against six human cancer cell lines. Some of these analogues have shown promising anticancer activity.
- Kamal, Ahmed,Ashwini Kumar,Arifuddin,Dastidar, Sunanda G
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p. 5135 - 5142
(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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- Method for preparing 4'-Demethylepipodophyllotoxin from podophyllotoxin
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A method for synthesizing a 4'-demethylepipodophyllotoxin of formula (II) from a podophyllotoxin of formula (I) by treating it with a pair of reagents, i.e. a strong acid and an aliphatic, aromatic or functionalized sulphide, in the present of an organic or inorganic acid, or in the presence of water with or without a water-miscible organic solvent. STR1
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- A facile and efficient synthesis of 4β-aminopodophyliotoxins
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4β-amino-4-desoxypodophyllotoxin and 4β-amino-4'-desmethyl-4- desoxypodophyllotoxin have been synthesized by reduction of the corresponding 4β-azidopodophyllotoxin derivatives with samarium diiodide in excellent yields under convenient and mild conditions.
- Yu, Yong-Ping,Chen, Shao-Yuan,Wang, Yan-Guang,Chen, Yao-Zu
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p. 1967 - 1970
(2007/10/03)
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- Synthesis and antitumor activity of new glycosides of epipodophyllotoxin, analogues of etoposide, and NK 611
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A series of 3-amino- and 3-alkylamino-2-deoxy-β-D-ribo- and β-D- arabino-glycosides of 4'-demethylepipodophyllotoxin have been synthesized by means of an improved trimethylsilyl-iodide procedure for the podophyllotoxin- 4'-demethylepipodophyllotoxin conversion, an efficient and high yielding synthesis of silyl glycoside donors of 3-azido-2,3-dideoxy-β-D-ribo-and β- D-arabino-hexopyranosides and stereoselective glycosylations. In vitro evaluation of cytotoxic effects against murine L1210 leukemia critically demonstrates the essential role played by a 4,6-acetal for biological activity. Among the most cytotoxic compounds, 3-amino-2,3-dideoxy-and 3-N,N- (dimethylamino)-2,3-dideoxy etoposide analogues, 17 and 27-29 are at least as potent as etoposide on the in vivo P388 (iv/ip) murine leukemia models. However, surprisingly enough, none of these compounds inhibits the human DNA topoisomerases I or II or binds to tubulin to prevent its polymerization and microtubule assembly. Therefore, their mechanism of action remains to be cleared up.
- Daley, Laurent,Guminski, Yves,Demerseman, Pierre,Kruczynski, Anna,Etiévant, Chantal,Imbert, Thierry,Hill, Bridget T.,Monneret, Claude
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p. 4475 - 4485
(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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- Stereo and chemoselective enzymatic reduction of azido functionality: Synthesis of 4-β-Aminopodophyllotoxin congeners by Baker's yeast
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4β-Aminopodophyllotoxin congeners have been synthesized by the stereoselective biocatalytic reduction of the 4-azidopodophyllotoxins employing baker's yeast in excellent yields under mild conditions.
- Kamal, Ahmed,Laxminarayana,Gayatri, N. Lakshmi
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p. 6871 - 6874
(2007/10/03)
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- An efficient method for 4β-anilino-4'-demethylepipodophyllotoxins: Synthesis of NPF and W-68
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4β-Substituted podophyllotoxin congeners have been obtained with significant stereoselectivity and improved yields by employing Bu4N+I in the displacement reaction of the 4-bromoepipodophyllotoxin. The DNA topoisomerase II inhibitors, NPF and W-68 have been prepared in good yields by this method.
- Kamal,Gayatri
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p. 3359 - 3362
(2007/10/03)
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- Immunosuppressive cyclolignans
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The immunosuppressive activity of several lactonic, nonlactonic, and heterocycle-fused cyclolignans has been demonstrated for the first time by use of a T-cell-mediated immune response. Of the compounds tested, 4'- demethyldeoxypodophyllotoxin (8), β-apopicropodophyllin (6), and the isoxazoline-fused cyclolignan 15 are the most potent with respect to their suppression of activated splenocytes.
- Gordaliza, Marina,Faircloth, Glynn T.,Castro, Ma. Angeles,Miguel Del Corral, José M.,López-Vázquez, Ma. Luisa,San Feliciano, Arturo
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p. 2865 - 2868
(2007/10/03)
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- New compounds related to podophyllotoxin and congeners: synthesis, structure elucidation and biological testing.
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4-Azido, 4-amino, 4-amido and 4-alkoxy compounds related to the lignans podophyllotoxin and 4'-demethylepipodophyllotoxin have been synthesized, and their structures elucidated. The Ritter reaction was shown to be useful in the preparation of the 4-amido compounds with the required stereochemistry. A preparative method for 4-chloro-4-deoxypicrophyllotoxin, for which all earlier synthetic attempts resulted in the two dehydrated compounds, alpha- and beta-apopicropodophyllotoxin, was developed. Supplementary preliminary studies of the biological activities of some of the compounds were performed. All compounds had pronounced inhibitory effect on the in vitro growth of human cervical cancer cells and TC-mouse cells with 4-amino-4-deoxypodophyllotoxin and 4-azido-4-deoxypodophyllotoxin showing the highest activity. Alkaline elution studies indicate that the toxicity of the 4'-demethoxy derivatives is due to protein-mediated DNA nicking. None of the compounds were found to have antiviral effect against herpes simplex type 2 (HSV-2), human immunodeficiency (HIV), and cytomegalovirus (CMV) in doses not toxic to the cells.
- Hansen,Jensen,Willumsen,Norskov-Lauritsen,Ebbesen,Nielsen,Buchardt
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p. 1190 - 1200
(2007/10/02)
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- Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and α-peltatin
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A principal mechanism of action of the clinical antitumor drugs etoposide (1) and teniposide (2) is the inhibition of catalytic activity of type II DNA topoisomerase and concurrent enzyme-mediated production of lethal DNA strand breaks. Substitution of the glycosidic moiety of 1 or 2 by ester and ethers, as well as the esterification and etherification of α-peltatin (4) including its glucosidic ethylidene and thenylidene cyclic acetals (25 and 26), has afforded compounds of much less activity than that of 1. The in vitro cytotoxicity (KB) appears to have no correlation with the inhibitory activity of the human DNA topoisomerase II.
- Thurston,Imakura,Haruna,Li,Liu,Liu,Cheng,Lee
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p. 604 - 608
(2007/10/02)
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- Syntheses of All Four Possible Diastereomers of Etoposide and Its Aminoglycosidic Analogues via Optical Resolution of (+/-)-Podophyllotoxin by Glycosidation with D- and L-Sugars
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Syntheses of all four possible diastereomers of etoposide and its aminoglycosidic analogues have been achieved via optical resolution of (+/-)-podophyllotoxin by glycosidation with D- and L-sugars.
- Saito, Hitoshi,Nishimura, Yoshio,Kondo, Shinichi,Umezawa, Hamao
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p. 799 - 802
(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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