- 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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Read Online
- Synthesis, antitumor activity, and molecular docking of (?)-epigallocatechin-3-gallate-4β-triazolopodophyllotoxin conjugates
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Two new (?)-epigallocatechin-3-gallate-4β-triazolopodophyllotoxin conjugates (7 and 8) were synthesized and evaluated for biological activity. Compound 8 showed highly potent anticancer activity against A-549 cell line with IC50 of 2.16 ± 1.02
- Zi, Cheng-Ting,Yang, Liu,Hu, Yue,Zhang, Pan,Tang, Han,Zhang, Bang-Lei,Shen, Xiao-Jing,Kong, Qing-Hua,Wang, Ya,Wang, Xuan-Jun,Sheng, Jun
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- Synthesis and antitumor activity of camptothecin- 4β-triazolopodophyllotoxin conjugates
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Two new compounds (9 and 10) having a camptothecin (CPT) analog conjugated to the 4β-azido-4-deoxypodophyllotixin analog by untilizing the copper-catalyzed azide-alkyne cycloadditon (CuAAC) reaction, and were evaluated for their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) using the MTT (3-(4,5-dimethyl-thiahiazo-2-yl)-2,5-diphenyltetrazolium bromide) assay. Two novel conjugates shown weak cytotoxicity, compound 10 showed highly potent against HL-60 cell line tested, with IC50 value 17.69 ± 0.19 μM. This compound suggested its potential as anticancer agents for further development. (Figure presented.).
- Ding, Zhong-Tao,Dong, Fa-Wu,Hu, Jiang-Miao,Jiang, Zi-Hua,Kong, Qing-Hua,Yang, Liu,Zhou, Jun,Zi, Cheng-Ting
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Read Online
- 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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- Synthesis and Cytotoxicity of Heterocyclic Amine Derivatives of Podophyllotoxin
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A series of amine podophyllotoxin derivatives was designed and synthesized by aldehydes reacting with 4β-amino-desoxypodophyllotoxin or 4′-demethyldesoxypodophyllotoxin. The MTT assay was used to test the cytotoxic activity of 11 target compounds on HeLa
- Chen, Hong,Liang, Chun-po,Luo, Gang,Tian, Dan-li
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p. 994 - 999
(2020/11/18)
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- ORGANOPLATINUM COMPOUNDS AND PHARMACEUTICAL COMPOSITION THEREOF AND METHOD OF PREPARING CRYSTAL OF hTop2
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Some organoplatinum compounds have been synthesized. These organoplatinum compounds are designed to be human Topoisomerase II-targeting drugs.
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Paragraph 0063-0064; 0088-0090
(2020/10/21)
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- HUMAN TOPOISOMERASE II-TARGETING ORGANOPLATINUM COMPOUNDS
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Some organoplatinum compounds have been synthesized. These organoplatinum compounds are designed to be human Topoisomerase II-targeting drugs.
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Paragraph 0083-0084; 0108-0109
(2020/03/15)
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- Novel conjugates of podophyllotoxin and coumarin: Synthesis, cytotoxicities, cell cycle arrest, binding CT DNA and inhibition of Topo IIβ
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A series of conjugates of podophyllotoxin and coumarin were prepared using the click reaction, and their cytotoxicities against A549, HepG2, HeLa, and LoVo cells were evaluated. Among them, compound 14e exhibited the strongest cytotoxicities against these cancer cells with IC50 values of 4.9–17.5 μM. Furthermore, 14e disrupted microtubules and induced cell cycle arrest at G1 phase by regulating P21 and Cyclin D1 in LoVo cells. In addition, 14e bond CT DNA and selectively inhibited Topo IIβ over Topo IIα. Molecular docking model showed that 14e appeared to form stable hydrogen bonds with several DNA bases and residue Gln778. Taken together, these conjugates have the potential to be developed as anti-tumor drugs.
- Hao, Shu-Yi,Feng, Shi-Liang,Wang, Xing-Rong,Wang, Zhichao,Chen, Shi-Wu,Hui, Ling
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supporting information
p. 2129 - 2135
(2019/07/05)
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- Podophyllotoxin compound containing 1,2,4-triazone structure, and application thereof
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The invention discloses a podophyllotoxin compound containing a 1,2,4-triazone structure, and an application thereof. The compound has a structure represented by general formula (I). Podophyllotoxin derivatives containing 1,2,4-triazone, represented by th
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Paragraph 0042; 0043
(2018/03/26)
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- A podophyllotoxin with norcantharidin of joining together and its preparation and use (by machine translation)
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The invention discloses a novel podophyllotoxin and norcantharidin of joining together, and this method for preparing compound and use thereof. The compounds of this invention is to go to a imide base carboxylic acid 4 β - amino -4 ' - to a epipodophyllot
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Paragraph 0028; 0029
(2017/07/11)
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- Micromolecular lung targeting medicine
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The invention discloses a micromolecular lung targeting medicine shown as a general formula I in the specification and relates to a compound of the general formula I or medically acceptable salts of the compound and a preparation prepared from the compoun
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Paragraph 0035; 0036; 0037
(2016/12/01)
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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 0042-0043
(2016/10/10)
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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 new podophyllotoxin derivatives with in vitro anticancer activity
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A series of novel podophyllotoxin derivatives were designed and synthesized. The cytotoxic activities of these compounds were tested against three tumor cell lines (HeLa, K562, and K562/A02). Most of the derivatives (IC50 = 1-20 μM) were found
- Cheng, Wei-Hua,Shang, Hai,Niu, Cong,Zhang, Zhong-Heng,Zhang, Li-Ming,Chen, Hong,Zou, Zhong-Mei
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p. 12266 - 12279
(2015/08/06)
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- Design, synthesis and cytotoxic activity of novel sulfonylurea derivatives of podophyllotoxin
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Three series of novel sulfonylurea podophyllotoxin derivatives were designed, synthesized, and evaluated for in vitro cytotoxicity against four tumor cell lines (A-549, DU-145, KB and KBvin). Compounds 14c (IC50: 1.41-1.76 μM) and 14e (IC5
- Zhang, Zhi-Jun,Tian, Jing,Wang, Li-Ting,Wang, Mei-Juan,Nan, Xiang,Yang, Liu,Liu, Ying-Qian,Morris-Natschke, Susan L.,Lee, Kuo-Hsiung
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supporting information
p. 204 - 210
(2014/01/17)
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- A rational design strategy of the novel topoisomerase II inhibitors for the synthesis of the 4-O-(2-pyrazinecarboxylic)-4′-demethylepipodophyllotoxin with antitumor activity by diminishing the relaxation reaction of topoisomerase II-DNA decatenation
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A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4′-demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential ant
- Zhao, Wei,Chen, Lu,Li, Hong-Mei,Wang, Duan-Ji,Li, Dong-Sheng,Chen, Tao,Yuan, Zhan-Peng,Tang, Ya-Jie
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p. 2998 - 3007
(2014/05/20)
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- Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin-N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA
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Drugs that target DNA topoisomerase II isoforms and alkylate DNA represent two mechanistically distinct and clinically important classes of anticancer drugs. Guided by molecular modeling and docking a series of etoposide analog epipodophyllotoxin-N-mustar
- Yadav, Arun A.,Wu, Xing,Patel, Daywin,Yalowich, Jack C.,Hasinoff, Brian B.
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p. 5935 - 5949
(2015/02/02)
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- Synthesis and evaluation of novel podophyllotoxin derivatives as potential antitumor agents
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Cancer multidrug resistance (MDR) is a common cause of treatment failure in cancer patients. Increased expression of permeability glycoprotein (P-gp), which is also known as MDR-1, is the main cause of multidrug resistance. Podophyllotoxin derivatives hold great promise in the battle to overcome multidrug resistance, as they can induce cytotoxicity through multiple mechanisms. Here, we synthesized sixteen novel podophyllotoxin derivatives and evaluated their cytotoxicities in human cancer cell lines, HeLa, K562 and K562/A02. Some of these compounds were more potent than etoposide, a clinically relevant inhibitor of DNA repair enzymes. In particular, compound 5p exhibited the most potent activity toward drug-resistant K562/A02 cells, as it robustly inhibited tumor cell proliferation and induced apoptosis. Furthermore, preliminary investigation suggested that 5p inhibited the expression of MDR-1 in K562/A02 cells more effectively than etoposide.
- Cheng, Wei-Hua,Cao, Bo,Shang, Hai,Niu, Cong,Zhang, Li-Ming,Zhang, Zhong-Heng,Tian, Dan-Li,Zhang, Shi,Chen, Hong,Zou, Zhong-Mei
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p. 498 - 507
(2014/09/16)
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- Synthesis and biological evaluation of novel 4β-(1,3,4-oxadiazole-2- amino)-podophyllotoxin derivatives
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A series of new 4β-(1,3,4-oxadiazole-2-amino)-podophyllotoxin derivatives were designed and synthesized. Their cytotoxicity in vitro against six tumor cell lines (DU-145, SGC-7901, A549, SH-SY5Y, HepG2 and HeLa) were evaluated by standard MTT assay. The p
- Ren, Jie,Wu, Lin,Xin, Wen Qun,Chen, Xin,Hu, Kun
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supporting information; experimental part
p. 4778 - 4782
(2012/08/13)
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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 antitumor activity of novel podophyllotoxin derivatives against multidrug-resistant cancer cells
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Seven novel 4-N-substituted podophyllotoxin derivatives with indole rings were prepared and evaluated for cytotoxicity against human cancer cell lines HeLa, KB, KBV, K562, and K562/AO2. Most of them demonstrated improved antitumor activity and weak multidrug resistance compared to the drugs currently available.
- Guo, Yong-En,Chen, Hong,Zuo, Song,Liu, Dai-Lin,Lu, Yan-Ling,Lv, Jing-Jing,Wen, Shao-Peng,Zhang, Tong-Cun
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scheme or table
p. 417 - 424
(2011/07/29)
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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 6-7
(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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- Antitumor agents. Part 227: Studies on novel 4′-O-demethyl- epipodophyllotoxins as antitumor agents targeting topoisomerase II
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Eight novel epipodophyllotoxin derivatives (6-13), which were designed to overcome drug resistance and enhance topoisomerase II inhibition, were synthesized and evaluated. Two of these compounds (7 and 8) showed better preclinical activity profiles, inclu
- Xiao, Zhiyan,Bastow, Kenneth F.,Vance, John R.,Lee, Kuo-Hsiung
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p. 3339 - 3344
(2007/10/03)
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- Synthesis of 4beta-amido and 4beta-sulphonamido analogues of podophyllotoxin as potential antitumour agents.
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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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- 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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- 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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- 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. 120. New 4-substituted benzylamine and benzyl ether derivatives of 4'-O-demethylepipodophyollotoxin as potent inhibitors of human DNA topoisomerase II
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A number of new 4'-O-demethylepipodophyllotoxin derivatives possessing various 4β-N- or 4β-O-benzyl groups have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The 4β-N-benzyl derivatives 9-22 are, in general, as active or more active than etoposide (1). The most active compounds are 14, 16, and 17, which are more than 2-fold more potent than 1. The results indicated that a basic unsubstituted 4β-benzylamino moiety is structurally required for the enhanced activity. Replacement of the benzyl nitrogen with oxygen gave compounds (23 and 24) which are inactive. The ability of these compounds to inhibit human DNA topoisomerase II and to cause protein-linked DNA breakage appears to have no direct correlation with cytotoxicity in KB cells.
- Zhou,Wang,Chang,Chen,Cheng,Lee
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p. 3346 - 3350
(2007/10/02)
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