- Identification of Pyruvate Carboxylase as the Cellular Target of Natural Bibenzyls with Potent Anticancer Activity against Hepatocellular Carcinoma via Metabolic Reprogramming
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Cancer cell proliferation in some organs often depends on conversion of pyruvate to oxaloacetate via pyruvate carboxylase (PC) for replenishing the tricarboxylic acid cycle to support biomass production. In this study, PC was identified as the cellular target of erianin using the photoaffinity labeling-click chemistry-based probe strategy. Erianin potently inhibited the enzymatic activity of PC, which mediated the anticancer effect of erianin in human hepatocellular carcinoma (HCC). Erianin modulated cancer-related gene expression and induced changes in metabolic intermediates. Moreover, erianin promotes mitochondrial oxidative stress and inhibits glycolysis, leading to insufficient energy required for cell proliferation. Analysis of 14 natural analogs of erianin showed that some compounds exhibited potent inhibitory effects on PC. These results suggest that PC is a cellular target of erianin and reveal the unrecognized function of PC in HCC tumorigenesis; erianin along with its analogs warrants further development as a novel therapeutic strategy for the treatment of HCC.
- Sheng, Yuwen,Chen, Yuwen,Zeng, Zhongqiu,Wu, Wenbi,Wang, Jing,Ma, Yuling,Lin, Yuan,Zhang, Jichao,Huang, Yulan,Li, Wenhua,Zhu, Qiyu,Wei, Xiao,Li, Suiyan,Wisanwattana, Wisanee,Li, Fu,Liu, Wanli,Suksamrarn, Apichart,Zhang, Guolin,Jiao, Wei,Wang, Fei
-
p. 460 - 484
(2022/01/03)
-
- Coumarins by Direct Annulation: β-Borylacrylates as Ambiphilic C3-Synthons
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Modular β-borylacrylates have been validated as programmable, ambiphilic C3-synthons in the cascade annulation of 2-halo-phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2)–C(sp2) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre-condition to access 3-substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π-expanded estrone derivatives modified at the A-ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.
- Wienhold, Max,Molloy, John J.,Daniliuc, Constantin G.,Gilmour, Ryan
-
supporting information
p. 685 - 689
(2020/11/30)
-
- Synthesis and Cytotoxicity Studies of Stilbene Long-Chain Fatty Acid Conjugates
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A series of 16 conjugates of the tubulin polymerization inhibitor combretastatin A4 (CA-4) and other functionally related stilbene with four 18-carbon fatty acids, namely, stearic, oleic, linoleic, and linolenic acids, have been synthesized in good yields. These new derivatives have been evaluated against the KB-3-1 (human epidermoid carcinoma), NCI-H460 (human lung cancer), HEK293 (human embryonic kidney), and MCF-7 (human breast adenocarcinoma) cell lines for antiproliferative activity, with the exhibited cytotoxic activities comparable with those of CA-4 and colchicine. Compounds 22 and 23, CA-4 conjugates of linoleic and linolenic acids, respectively, were determined to have exhibited the most active in vitro assays, with compound 23 exhibiting very similar activity to the parent compound against the NCI-H460 cell line. Our studies further delineated the structurally required Z-geometry of the stilbene moiety and that conjugation of the less active E-stilbenes with the most active fatty acid had minimal or no improvement in their respective activities.
- Brown, David P.,Chen, Zhe-Sheng,Narayanan, Silpa,Wong, Thomas
-
-
- Bioreductively Activatable Prodrug Conjugates of Combretastatin A-1 and Combretastatin A-4 as Anticancer Agents Targeted toward Tumor-Associated Hypoxia
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The natural products combretastatin A-1 (CA1) and combretastatin A-4 (CA4) function as potent inhibitors of tubulin polymerization and as selective vascular disrupting agents (VDAs) in tumors. Bioreductively activatable prodrug conjugates (BAPCs) can enha
- Chaplin, David J.,Davis, Peter,Devkota, Laxman,Gerberich, Jeni L.,Hamel, Ernest,Kuch, Bunnarack,Macdonough, Matthew T.,Mason, Ralph P.,Mondal, Deboprosad,Pinney, Kevin G.,Ramirez, Alejandro J.,Shi, Zhe,Strecker, Tracy E.,Trawick, Mary Lynn,Wang, Yifan,Winn, Blake A.
-
-
- Microtubule inhibitors containing immunostimulatory agents promote cancer immunochemotherapy by inhibiting tubulin polymerization and tryptophan-2,3-dioxygenase
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A combination therapeutic regimen via introducing tryptophan 2,3-dioxygenase inhibitors into microtubule inhibitors was performed and evaluated for their antitumor activity. Thereinto, HT2, composed of combretastatin A-4 (CA-4) and tryptophan-2,3-dioxygenase (TDO) inhibitor by a linker, displayed the most potent activity with 10-fold higher than its parent CA-4 against HepG2, A549 and HCT-116 cancer cell lines. Mechanism studies suggested that HT2 inhibited tubulin polymerization and cell migration, caused G2 phase arrest, induced apoptosis by mitochondrial mediated apoptotic pathway, concurrent depolarized the mitochondria membrane potentials and caused reactive oxygen species (ROS) production in HepG2 cells. Moreover, HT2 could enhance T-cell immune responses in vitro by releasing a TDO inhibitor to suppress TDO expression and blockade kynurenine production. As expected, HT2 could remarkably promote the antitumor activity of CA-4 in either immunocompetent H22 or immunodeficient A549 tumor xenograft models without observable toxic effects. More importantly, HT2 increased the level of splenic and tumor-infiltrated T cells and in turn effectively boosted the inhibition effect in H22 xenografted tumor growth. Collectively, this immunochemotherapeutic strategy can be applied to promote chemotherapeutic effect.
- Hua, Shixian,Chen, Feihong,Gou, Shaohua
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supporting information
(2019/12/11)
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- Dual-functional conjugates improving cancer immunochemotherapy by inhibiting tubulin polymerization and indoleamine-2,3-dioxygenase
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A series of novel conjugates comprising tublin and IDO inhibitors were designed, synthesized and evaluated for their antiproliferative activity. Among them, HI5, composed of combretastatin A-4 (CA-4) and (D)-1-methyltryptophan (D-MT) by a linker, exhibited the most potent antitumor activity, in particular with higher IC50 value (0.07 μM) than CA-4 (0.21 μM) against HeLa cancer cell line. Mechanism studies indicated that HI5 can inhibit tubulin polymerization and cell migration, cause G2/M phase arrest, concurrent induce apoptosis via the mitochondrial dependent apoptosis pathway and cause reactive oxidative stress generation in HeLa cells. Furthermore, HI5 can inhibit IDO expression and decrease kynurenine production, leading to stimulating T cells activation and proliferation to enhance antitumor immunity in vitro. Interestingly, HI5 can effectively limit the tumor growth in the HeLa xenograft mice models without causing significant loss of body weight. Consequently, such a conjugation can be a potent and safe immunochemotherapeutic method for improving cancer therapy.
- Chen, Feihong,Gou, Shaohua,Hua, Shixian,Wang, Xinyi
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supporting information
(2020/01/21)
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- Synthesis, Biological Evaluation, and Molecular Docking of Combretastatin and Colchicine Derivatives and their hCE1-Activated Prodrugs as Antiviral Agents
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Recent studies indicate that tubulin can be a host factor for vector-borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub-micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.
- Richter, Michael,Boldescu, Veaceslav,Graf, Dominik,Streicher, Felix,Dimoglo, Anatoli,Bartenschlager, Ralf,Klein, Christian D.
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p. 469 - 483
(2019/02/01)
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- Prodrug Activation by a Viral Protease: Evaluating Combretastatin Peptide Hybrids to Selectively Target Infected Cells
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Infections with flaviviruses such as dengue virus (DENV) are prevalent throughout tropical regions worldwide. Replication of these viruses depends on tubulin, a host cell factor that can be targeted to obtain broad-spectrum antiviral agents. Targeting of tubulin does, however, require specific measures to avoid toxic side-effects. Herein, we report the synthesis and biological evaluation of combretastatin peptide hybrids that incorporate the cleavage site of the DENV protease to allow activation of the tubulin ligand within infected cells. The prodrug candidates have no effect on tubulin polymerization in vitro and are 20-2000-fold less toxic than combretastatin A-4. Several of the prodrug candidates were cleaved by the DENV protease in vitro with similar efficiency as the natural viral substrates. Selected compounds were studied in DENV and Zika virus replication assays and had antiviral activity at subcytotoxic concentrations.
- Richter, Michael,Leuthold, Mila M.,Graf, Dominik,Bartenschlager, Ralf,Klein, Christian D.
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p. 1115 - 1121
(2019/08/20)
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- Pt(IV) prodrugs containing microtubule inhibitors displayed potent antitumor activity and ability to overcome cisplatin resistance
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It is well-known that cisplatin exhibited a broad spectrum of anticancer activities against many solid tumors, but its severe toxicity and drug resistance have largely limited wider clinical applications. Various strategies have been tried to discover new Pt (II) drugs with at least equal activity as well as low toxicity compared to cisplatin, but the inherent problem remains unsolved. Here we report that Pt (IV) complexes comprising a CA-4 analogue, as dual-targeting Pt (IV) prodrug, were synthesized and evaluated for anti-proliferative activity using MTT assay. Among them, complex 19 displayed most potent activity against the tested cancer cell lines, and simultaneously exhibited better cell selectivity between cancer cells and normal cells than that of cisplatin. Mechanism studies revealed that complex 19 effectively induced cell cycle arrest at the G2/M phase and dramatically disrupted the microtubule organization. Moreover, complex 19 significantly induced cell apoptosis and decreased MMP. Importantly, complex 19 significantly inhibited tumor growth in SK-OV-3 xenograft model in vivo without apparent toxicity.
- Li, Lingxue,Huang, Xiaochao,Huang, Rizhen,Gou, Shaohua,Wang, Zhimei,Wang, Hengshan
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p. 666 - 679
(2018/07/29)
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- Neuroprotective and Antineuroinflammatory Effects of Hydroxyl-Functionalized Stilbenes and 2-Arylbenzo[b]furans
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The drugs currently used to treat Alzheimer’s disease (AD) are limited in the benefits they confer, and no medication has been clearly proven to cure or delay the progression of AD. Most candidate AD drugs are meant to reduce the production, aggregation,
- Chen, Pei-Chun,Tsai, Wei-Jern,Ueng, Yune-Fang,Tzeng, Tsai-Teng,Chen, Hsiang-Ling,Zhu, Pei-Ru,Huang, Chia-Hsiang,Shiao, Young-Ji,Li, Wen-Tai
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p. 4062 - 4073
(2017/05/19)
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- Combretastatin A-4 Analogue: A Dual-Targeting and Tubulin Inhibitor Containing Antitumor Pt(IV) Moiety with a Unique Mode of Action
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Three new Pt(IV) complexes comprising a combretastatin A-4 analogue were designed and synthesized. The resulting antitumor Pt(IV) complexes could significantly improve the antiproliferative activity and overcome the drug resistance of cisplatin in vitro. Interestingly, these novel compounds not only can carry the DNA binding Pt(II) warhead into the cancer cells but also have a small molecule fragment that can inhibit tubulin polymerization. Among them, complex 13, which was attached to an inhibitor of tubulin at one axial position of Pt(IV) octahedral coordination sphere, could effectively enter cancer cells, arrest the cell cycle in HepG-2 cancer cells at G2/M phases, and induce activation of caspases triggering apoptotic signaling via the mitochondrial-dependent apoptosis pathways. Moreover, complex 13 has the ability to effectively inhibit the tumor growth in the HepG-2 xenograft model without causing significant loss of animal body weight in comparison with cisplatin.
- Huang, Xiaochao,Huang, Rizhen,Gou, Shaohua,Wang, Zhimei,Liao, Zhixin,Wang, Hengshan
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p. 2132 - 2148
(2016/09/28)
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- Design, synthesis, and biological evaluation of water-soluble amino acid prodrug conjugates derived from combretastatin, dihydronaphthalene, and benzosuberene-based parent vascular disrupting agents
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Targeting tumor vasculature represents an intriguing therapeutic strategy in the treatment of cancer. In an effort to discover new vascular disrupting agents with improved water solubility and potentially greater bioavailability, various amino acid prodru
- Devkota, Laxman,Lin, Chen-Ming,Strecker, Tracy E.,Wang, Yifan,Tidmore, Justin K.,Chen, Zhi,Guddneppanavar, Rajsekhar,Jelinek, Christopher J.,Lopez, Ramona,Liu, Li,Hamel, Ernest,Mason, Ralph P.,Chaplin, David J.,Trawick, Mary Lynn,Pinney, Kevin G.
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p. 938 - 956
(2016/02/19)
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- Development of Tetrachlorophthalimides as Liver X Receptor β (LXRβ)-Selective Agonists
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Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP-binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP-1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ-selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand-binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ-selective agonist. Structural development led to (E)-4,5,6,7-tetrachloro-2-(2-styrylphenyl)isoindoline-1,3-dione (24 a), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP-1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists.
- Nomura, Sayaka,Endo-Umeda, Kaori,Makishima, Makoto,Hashimoto, Yuichi,Ishikawa, Minoru
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p. 2347 - 2360
(2016/10/25)
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- Synthesis and anti-inflammatory activity of phenylbutenoid dimer analogs
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Several phenylbutenoid dimer (PBD) analogs were synthesized and evaluated for their inhibitory activities against nitric oxide (NO) production and TNF-α release. The PBD analogs were synthesized via Diels - Alder and subsequent Schlosser reactions as key steps. Among the tested compounds, two analogs (8c, 8f) exhibited much stronger inhibitory activity against LPS-stimulated NO production and TNF-α release in RAW 264.7 cells than that of wogonin.
- Kim, Sung-Soo,Fang, Yuanying,Park, Haeil
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supporting information
p. 1676 - 1680
(2015/07/15)
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- Cytotoxic activities and metabolic studies of new combretastatin analogues
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A new series of combretastatin analogues with B-ring modifications were synthesized and evaluated for their cytotoxicity against one endothelial (HUVEC) and three tumor cell lines, e.g., the LoVo colon, the PC-3 prostate, and the U373 glioma cancer models. These new combretastatin analogues showed differential cytotoxic activities, cis derivatives 13 5-(2-Z-trimethoxyphenylethenyl)benzo[1,2-c]1,2,5-oxadiazole N 1-oxide and 14 5-(2-Z-trimethoxyphenylethenyl)benzo[1,2,5]thiadiazole exhibiting interesting cytotoxicity both on endothelial and on tumor cells. Unlike the cis benzofurazan 12 5-(2-Z-trimethoxyphenylethenyl)benzo[1,2-c]1,2,5-oxadiazole, induction of apoptosis by 13 appeared to be through caspase-3 activation. Metabolic investigations showed a positive correlation between highly metabolized compounds and cytotoxic activity, suggesting that highly cytotoxic derivatives may act as pro-drug via a reductive metabolization to more active metabolites.
- Macé, Yohan,Bony, Emilie,Delvaux, David,Pinto, Adan,Mathieu, Véronique,Kiss, Robert,Feron, Olivier,Quetin-Leclercq, Jo?lle,Riant, Olivier
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p. 3143 - 3156
(2015/08/03)
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- Styrylphenylphthalimides as Novel Transrepression-Selective Liver X Receptor (LXR) Modulators
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Anti-inflammatory effects of liver X receptor (LXR) ligands are thought to be largely due to LXR-mediated transrepression, whereas side effects are caused by activation of LXR-responsive gene expression (transactivation). Therefore, selective LXR modulators that preferentially exhibit transrepression activity should exhibit anti-inflammatory properties with fewer side effects. Here, we synthesized a series of styrylphenylphthalimide analogues and evaluated their structure-activity relationships focusing on LXRs-transactivating-agonistic/antagonistic activities and transrepressional activity. Among the compounds examined, 17l showed potent LXR-transrepressional activity with high selectivity over transactivating activity and did not show characteristic side effects of LXR-transactivating agonists in cells. This representative compound, 17l, was confirmed to have LXR-dependent transrepressional activity and to bind directly to LXRβ. Compound 17l should be useful not only as a chemical tool for studying the biological functions of LXRs transrepression but also as a candidate for a safer agent to treat inflammatory diseases.
- Nomura, Sayaka,Endo-Umeda, Kaori,Aoyama, Atsushi,Makishima, Makoto,Hashimoto, Yuichi,Ishikawa, Minoru
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supporting information
p. 902 - 907
(2015/08/24)
-
- Design and Synthesis of Aminostilbene-Arylpropenones as Tubulin Polymerization Inhibitors
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A series of aminostilbene - arylpropenones were designed and synthesized by Michael addition and were investigated for their cytotoxic activity against various human cancer cell lines. Some of the investigated compounds exhibited significant antiproliferative activity against a panel of 60 human cancer cell lines of the US National Cancer Institute, with 50% growth inhibition (GI50) values in the range from 50 value of 50) values ranging from 0.011 to 8.56μM. A cell cycle assay revealed that these compounds arrested the G2/M phase of the cell cycle. Two compounds exhibited strong inhibitory effects on tubulin assembly with IC50 values of 0.71 and 0.79μM. Moreover, dot-blot analysis of cyclinB1 demonstrated that some of the congeners strongly induced cyclinB1 protein levels. Molecular docking studies indicated that these compounds occupy the colchicine binding site of tubulin.
- Kamal, Ahmed,Kumar, G. Bharath,Polepalli, Sowjanya,Shaik, Anver Basha,Reddy, Vangala Santhosh,Reddy, M. Kashi,Reddy, Ch. Ratna,Mahesh, Rasala,Kapure, Jeevak Sopanrao,Jain, Nishant
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p. 2565 - 2579
(2015/08/24)
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- Synthesis of novel anticancer agents through opening of spiroacetal ring of diosgenin
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Diosgenin has been modified to furostane derivatives after opening the F-spiroacetal ring. The aldehyde group at C26 in derivative 8 was unexpectedly transformed to the ketone 9. The structure of ketone 9 was confirmed by spectroscopy and finally by X-ray crystallography. Five of the diosgenin derivatives showed significant anticancer activity against human cancer cell lines. The most potent molecule of this series i.e. compound 7, inhibited cellular growth by arresting the population at G0/G1 phase of cell division cycle. Cells undergo apoptosis after exposure to the derivative 7 which was evident by increase in sub G0 population in cell cycle analysis. Docking experiments showed caspase-3 and caspase-9 as possible molecular targets for these compounds. This was further validated by cleavage of PARP, a caspase target in apoptotic pathway. Compound 7 was found non-toxic up to 1000 mg/kg dose in acute oral toxicity in Swiss albino mice.
- Hamid,Hasanain, Mohammad,Singh, Arjun,Bhukya, Balakishan,Omprakash,Vasudev, Prema G.,Sarkar, Jayanta,Chanda, Debabrata,Khan, Feroz,Aiyelaagbe,Negi, Arvind S.
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p. 108 - 118
(2014/07/08)
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- Synthesis of combretastatin A4 analogues on steroidal framework and their anti-breast cancer activity
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Combretastatin A4 analogues were synthesized on steroidal framework from gallic acid with a possibility of anti-breast cancer agents. Twenty two analogues were synthesized and evaluated for cytotoxicity against human breast cancer cell lines (MCF-7 & MDA-MB 231). The best analogue 22 showed potent antitubulin effect. Docking experiments also supported strong binding affinity of 22 to microtubule polymerase. In cell cycle analysis, 22 induced apoptosis in MCF-7 cells significantly. It was found to be non-toxic up to 300 mg/kg dose in Swiss albino mice in acute oral toxicity. This article is part of a Special Issue entitled "Synthesis and biological testing of steroid derivatives as inhibitors".
- Parihar, Swati,Kumar, Amit,Chaturvedi, Amit K.,Sachan, Naresh Kumar,Luqman, Suaib,Changkija, Bendangla,Manohar, Murli,Prakash, Om,Chanda,Khan, Feroz,Chanotiya,Shanker, Karuna,Dwivedi, Anila,Konwar, Rituraj,Negi, Arvind S.
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p. 332 - 344
(2013/11/19)
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- A protecting group-free synthesis of the antineoplastic agent combretastatin A4
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The synthesis of combretastatin A4 (CA4) from commercially available inexpensive materials has been achieved via the Wittig reaction followed by irradiation of the (Z)/(E)-CA4 reaction mixture with sunlight. The method resulted in (Z)-CA4 in high yield. This method does not require protection of the phenolic hydroxy group. The synthesis is operationally simple and cost-efficient.
- Guo, Xiaotao,Zhang, Dan,Yu, Zhifang,Liu, Tianzhen,Li, Dachang,Li, Chunbao
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experimental part
p. 229 - 230
(2011/07/09)
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- Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl- thiazoles analogues as potent and orally bioavailable anticancer agents
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In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)).
- Lu, Yan,Li, Chien-Ming,Wang, Zhao,Chen, Jianjun,Mohler, Michael L.,Li, Wei,Dalton, James T.,Miller, Duane D.
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experimental part
p. 4678 - 4693
(2011/09/14)
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- COMPOUNDS FOR TREATMENT OF CANCER
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The present invention relates to novel compounds having anti-cancer activity, methods of making these compounds, and their use for treating cancer and drug-resistant tumors, e.g. melanoma, metastatic melanoma, drug resistant melanoma, prostate cancer and drug resistant prostate cancer.
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Paragraph 0037; 00304
(2011/10/03)
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- Inhibition of restriction enzymes EcoRI, BamHI and HindIII by phenethylphenylphthalimides derived from thalidomide
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We discovered inhibitors of the restriction enzymes EcoRI, BamHI and HindIII by screening our library of compounds with a phenethylphenylphthalimide skeleton, based on α-glucosidase inhibitors and liver X receptor antagonists derived from thalidomide. Str
- Motoshima, Kazunori,Ishikawa, Minoru,Hashimoto, Yuichi,Sugita, Kazuyuki
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experimental part
p. 880 - 884
(2011/08/04)
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- Design and in vitro evaluation of branched peptide conjugates: Turning nonspecific cytotoxic drugs into tumor-selective agents
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The use of peptide receptors as targets for tumor-selective therapies was envisaged years ago with the findings that receptors for different endogenous regulatory peptides are overexpressed in several primary and metastatic human tumors, and can be used as tumor antigens. Branched peptides can retain or even increase, through multivalent binding, the biological activity of a peptide and are very resistant to proteolysis, thus having a markedly higher in vivo activity compared with the corresponding monomeric peptides. Oligo-branched peptides, containing the human regulatory peptide neurotensin (NT) sequence, have been used as tumor-specific targeting agents. These peptides are able to selectively and specifically deliver effector units, for cell imaging or killing, to tumor cells that overexpress NT receptors. Results obtained with branched NT conjugated to different functional units for tumor imaging and therapy indicate that branched peptides are promising novel multifunctional targeting molecules. This study is focused on the role of the releasing pattern of drug-conjugated branched NT peptides. We present results obtained with oligobranched neurotensin peptides conjugated to 6-mercaptopurin (6-MP), combretastain A-4 (CA4) and monastrol (MON). Drugs were conjugated to oligo-branched neurotensin through different linkers, and the mode-of-release, together with cytotoxicity, was studied in different human cancer cell lines. The results show that branched peptides are very promising pharmacodelivery options. Among our drug-armed branched peptides, NT4-CA4 was identified as a candidate for further development and evaluation in preclinical pharmacokinetic and pharmacodynamic studies. This peptide-drug exhibits significant activity against pancreas and prostate human cancer cells. Consequently, this derivative is of considerable interest due to the high mortality rates of pancreas neuroendocrine tumors and the high incidence of prostate cancer.
- Falciani, Chiara,Brunetti, Jlenia,Pagliuca, Chiara,Menichetti, Stefano,Vitellozzi, Lucia,Lelli, Barbara,Pini, Alessandro,Bracci, Luisa
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scheme or table
p. 567 - 574
(2010/12/18)
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- Regio-and stereospecific synthesis of mono-β-d-glucuronic acid derivatives of combretastatin A-1
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Synthetic routes have been established for the preparation of regio-and stereoisomerically pure samples of the mono-β-d-glucuronic acid derivatives of combretastatin A-1, referred to as CA1G1 (5a) and CA1G2 (6a). Judicious choice of protecting groups for the catechol ring was required for the regiospecific introduction of the glucuronic acid moiety. The tosyl group proved advantageous in this regard. The two monoglucuronic acid analogues demonstrate low cytotoxicity (compared to CA1, 2) against selected human cancer cell lines, with CA1G1 being slightly more potent than CA1G2.
- Tanpure, Rajendra P.,Strecker, Tracy E.,Chaplin, David J.,Siim, Bronwyn G.,Trawick, Mary Lynn,Pinney, Kevin G.
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supporting information; experimental part
p. 1093 - 1101
(2010/09/09)
-
- Design and synthesis of novel pinacolylboronate containing combretastatin 'antimitotic agent' analogues
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We developed a procedure to synthesize pinacolyl boronate containing stilbene derivatives and used this procedure to synthesize boron-containing combretastatin analogues. The key step involves the Wittig reaction of the ylide 4-(4,4,5,5-tetramethyl-1,3,2-
- Das, Bhaskar C.,Mahalingam, Sakkarapalayam M.,Evans, Todd
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scheme or table
p. 3031 - 3034
(2009/10/04)
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- Synthesis of resveratrol, DMU-212 and analogues through a novel Wittig-type olefination promoted by nickel nanoparticles
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A novel synthesis of resveratrol, DMU-212 and analogues is presented using benzyl alcohols as phosphorus ylide partners in a one-pot Wittig-type olefination reaction promoted by nickel nanoparticles.
- Alonso, Francisco,Riente, Paola,Yus, Miguel
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body text
p. 3070 - 3073
(2009/10/04)
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- Wittig-type olefination of alcohols promoted by nickel nanoparticles: Synthesis of polymethoxylated and polyhydroxylated stilbenes
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Nickel nanoparticles were found to promote the Wittig-type olefination of primary alcohols with phosphorus ylides. The latter can be prepared from the corresponding phosphonium salts with TiBuLi or in situ generated with lithium metal. The methodology is especially efficient for the synthesis of stilbenes and is applied in the absence of any additive as a hydrogen acceptor. A new approach, to the synthesis of polymethoxylated and polyhydroxylated stilbenes, including resveratrol, DMU-212 and analogues, is presented.
- Alonso, Francisco,Riente, Paola,Yus, Miguel
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supporting information; experimental part
p. 6034 - 6042
(2010/02/28)
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- PROCESS FOR PREPARING ERIANIN
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A process for preparing Erianin (Dihydro Combretastation A-4), wherein 3,4,5-trimethoxy benzaldehyde is converted to phosphonium salt or phosphonate ester or the likes thereof, then reacted with isovanillin (3-hydroxyl-4-methoxyl benzaldehyde) including a protected hydroxyl in the 3-position, followed by hydrogenation and deprotection.
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Page/Page column 5
(2009/01/24)
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- Structure-activity relationship studies on a novel class of antiproliferative agents derived from Lavendustin A. Part I: Ring A modifications
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The potent antiproliferative agent SDZ LAP 977, which has shown efficacy in a clinical proof of concept study in actinic keratosis patients, has been previously demonstrated to block the cell cycle in mitosis. In the present study, we further explored the mode of action: SDZ LAP 977 binds to the "colchicine binding site" on tubulin and, thus, inhibits tubulin polymerization in vitro. Moreover, we established structure-activity relationships for the effect of modifications in the 2,5-dimethoxyphenyl moiety ("ring A") of the molecule on in vitro antiproliferative activity.
- Nussbaumer, Peter,Winiski, Anthony P.
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p. 7552 - 7560
(2008/12/23)
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- ERIANIN SALTS, THEIR PREPARATION METHODS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME
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This invention relates to a kind of Erianin salt and the preparing process thereof. The said Erianin salt is a compound with the following general formula (I), wherein R is the salt formed by monobasic acid radical of inorganic oxacid combining with metals, ammonium salts, organic amine. This invention also relates to a pharmaceutical composition comprising Erianin salt. Compared with Erianin, the said Erianin salt has far better solubility, which can improve the bioavailability and show better antineoplastic efficacy.
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- 3,4,5,4' - TETRAMETHOXYL- ALPHA,BETA-DIPHENYLETHANE -3' -0- SODIUMSULPHATE AND ITS USE
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This invention relates to a compound of formula (I), 3,4,5,4′-tetramethoxyl-α,β-diphenylethane-3′-O-sodium sulphate, and its use in the preparation of antineoplastic pharmaceutical.
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- USE OF ERIANIN IN PREPARING PHARMACEUTICAL FOR TREATING TUMORS
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This invention relates to a use of the compound of formula (I), Erianin, in preparing pharmaceutical for treating tumors
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- Combretastatin dinitrogen-substituted stilbene analogues as tubulin-binding and vascular-disrupting agents
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Several stilbenoid compounds having structural similarity to the combretastatin group of natural products and characterized by the incorporation of two nitrogen-bearing groups (amine, nitro, serinamide) have been prepared by chemical synthesis and evaluat
- Siles, Rogelio,Ackley, J. Freeland,Hadimani, Mallinath B.,Hall, John J.,Mugabe, Benon E.,Guddneppanavar, Rajsekhar,Monk, Keith A.,Chapuis, Jean-Charles,Pettit, George R.,Chaplin, David J.,Edvardsen, Klaus,Trawick, Mary Lynn,Garner, Charles M.,Pinney, Kevin G.
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experimental part
p. 313 - 320
(2009/04/11)
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- Further naphthylcombretastatins. An investigation on the role of the naphthalene moiety
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By synthesis and biological studies of new naphthalene analogues of combretastatins, we have found that the naphthalene is a good surrogate for the isovanillin moiety (3-hydroxy-4-methoxyphenyl) of combretastatin A-4, always generating highly cytotoxic analogues when combined with the 3,4,5-trimethoxyphenyl or related systems. On the other hand, when the naphthalene replaces the 3,4,5-trimethoxyphenyl moiety, the cytotoxic activity is largely decreased. The most cytotoxic naphthalene analogues of combretastatins, which also produce inhibition of tubulin polymerization, exerted their antimitotic effects through microtubule network disruption and subsequent G2/M arrest of the cell cycle in human cancer cells.
- Maya, Ana B. S.,Pérez-Melero, Concepción,Mateo, Carmen,Alonso, Dulce,Fernández, José Luis,Gajate, Consuelo,Mollinedo, Faustino,Peláez, Rafael,Caballero, Esther,Medarde, Manuel
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p. 556 - 568
(2007/10/03)
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- Synthesis and crystal structures of cis- and trans-1-(3′-N,N- dimethylthiocarbamoyl-4′-methoxy)-2-(3″, 4″, 5″-trimethoxyphenyl) ethene
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The combretastatin A-4 analogue cis-1-(3′-N,N-dimethylthiocarbamoyl- 4′-methoxy)-2-(3″,4″,5″-trimethoxyphenyl) ethene (1) and its trans stereoisomer (2) were synthesized. The molecular structures of these compounds were obtained by single-crystal X-ray di
- Ramirez, Daniel A.,Zhang, Jianxing,Klausmeyer, Kevin,Kane, Robert R.
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p. 227 - 232
(2007/10/03)
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- A new family of quinoline and quinoxaline analogues of combretastatins
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The 3-hydroxy-4-methoxyphenyl ring of combretastatin A-4 can be replaced by a 2-naphthyl moiety without significant loss of cytotoxicity and inhibition of tubulin polymerization potency. In this paper we show that the 6- or 7-quinolyl systems can in turn replace both cyclic moieties, keeping in the first case most of the potency as cytotoxic agent and in the second case as inhibitor of tubulin polymerization, related to the activities displayed by model compounds.
- Perez-Melero, Concepcion,Maya, Ana B.S.,Del Rey, Benedicto,Pelaez, Rafael,Caballero, Esther,Medarde, Manuel
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p. 3771 - 3774
(2007/10/03)
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- Functionalized stilbene derivatives as improved vascular targeting agents
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Novel stilbenoid compounds and their prodrug forms are disclosed, which serve as potent vascular targeting agents useful for the treatment of solid tumor cancers and other diseases associated with unwanted neovascularization. The novel stilbenoid compound
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- Synthesis and biological evaluation of aryl azide derivatives of combretastatin a-4 as molecular probes for tubulin
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Two new aryl azides, (Z)-1-(3'-azido-4'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 9 and (Z)-1-(4'-azido-3'-methoxyphenyl)-2-(3'',4'',5''-trimethoxyphenyl)ethene 5, modeled after the potent antitumor, antimitotic agent combretastatin A-4 (CA-4)
- Pinney, Kevin G.,Mejia, Maria P.,Villalobos, Victor M.,Rosenquist, Brent E.,Pettit, George R.,Verdier-Pinard, Pascal,Hamel, Ernest
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p. 2417 - 2425
(2007/10/03)
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- Synthesis of water-soluble prodrugs of the cytotoxic agent Combretastatin A4
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Water-soluble phosphate and glycine carbamate prodrugs of the cytotoxic agent Combretastatin A4 (1) have been prepared. The phosphate prodrug was degraded slowly in plasma at 37°C. The degradation was accelerated by the addition of alkaline phosphatase.
- Bedford, Simon B.,Quarterman, Charmaine P.,Rathbone, Daniel L.,Slack, John A.,Griffin, Roger J.,Stevens, Malcolm F. G.
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p. 157 - 160
(2007/10/03)
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- Potential photoaffinity labels for tubulin. Synthesis and evaluation of diazocyclohexadienone and azide analogs of colchicine, combretastatin, and 3,4,5-trimethoxybiphenyl
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Analogs of tubulin assembly inhibitors such as colchicine, combretastatin, and 3,4,5-trimethoxybiphenyl which incorporate a 6-diazo-2,4-cyclohexadienone (o-quinone diazide) ring have been synthesized and characterized. The compounds synthesized include 6-diazo-4-(2',3',4'-trimethoxyphenyl)cyclohexa-2,4-dien-1-one and its 3-methyl and 3-ethyl analogs (1a-c), 6-diazo-3-(2,3,4-trimethoxyphenyl)-2,4-cyclohexadien-1-one and its 4-methyl and 4-ethyl derivatives (2a-c), 4-[Z-2-(3',4',5'-trimethoxyphenyl)ethenyl]-6-diazocyclohexa-2,4-dienon e (3), 3-[Z-2-(3',4',5'-trimethoxyphenyl)ethenyl]-6-diazocyclohexa-2,4-dien-1 -one (4), the corresponding dihydro derivatives (5, 6) and two isomeric diazocyclohexadienones derived from N-acetylcolchinol (7, 8). Compounds in which the cyclohexadienone oxygen is approximately isostructural with carbonyl or hydroxy functions of the parent compounds exhibit good activity in the tubulin assembly inhibition assay. 2'-Alkyl-4'azido-3,4,5-trimethoxy-1,1'-biphenyls also show good activity as tubulin assembly inhibitors.
- Olszewski,Marshalla,Sabat,Sundberg
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p. 4285 - 4296
(2007/10/02)
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