- NFSI/KF mediated mild and chemoselective interconversion of aryl TBDMS ethers to their benzene sulfonate
-
A one pot protocol for the transformation of aryl TBDMS ethers to corresponding benzene sulfonate esters using NFSI (N-flurobenzenesulfonimide)/KF is described. In situ generation of benzenesulfonyl fluoride directs chemoselective cleavage of aryl silyl ethers over alkyl silyl ethers. Electron withdrawing substituent's on aryl ring provided better yield than donating groups. Protecting groups and sensitive functionalities are well tolerated in this methodology. Thus, commercially available inexpensive reagents, mild reaction conditions and step economy are the advantages of this method.
- Dond, Bharat D.,Thore, Shivaji N.
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supporting information
(2020/02/06)
-
- 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
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- 3-Vinylazetidin-2-Ones: Synthesis, antiproliferative and tubulin destabilizing activity in MCF-7 and MDA-MB-231 Breast Cancer Cells
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Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 μM for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.
- Wang, Shu,Malebari, Azizah M.,Greene, Thomas F.,O’Boyle, Niamh M.,Fayne, Darren,Nathwani, Seema M.,Twamley, Brendan,McCabe, Thomas,Keely, Niall O.,Zisterer, Daniela M.,Meegan, Mary J.
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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
-
supporting information
p. 666 - 679
(2018/07/29)
-
- Pd-Catalyzed Conjunctive Cross-Coupling between Grignard-Derived Boron “Ate” Complexes and C(sp2) Halides or Triflates: NaOTf as a Grignard Activator and Halide Scavenger
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Catalytic enantioselective conjunctive cross-couplings that employ Grignard reagents are shown to furnish an array of nonracemic chiral organoboronic esters in an efficient and highly selective fashion. The utility of sodium triflate in facilitating this reaction is two-fold: it enables “ate” complex formation and overcomes catalytic inhibition by halide ions.
- Lovinger, Gabriel J.,Aparece, Mark D.,Morken, James P.
-
supporting information
p. 3153 - 3160
(2017/03/11)
-
- To replace the double-aryl cycloalkyl derivatives and its preparation method and application
-
The invention provides a substituent bis-aryl methylene naphthenic base derivative with the structure of a general formula I, as well as medical salt or hydrate thereof. The class of compound can be used as micromolecule tubulin inhibitor, has a canalicul
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-
- Diaryl-beta-lactam compounds, and preparation method and application thereof in drug preparation
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The invention belongs to the field of synthetic pharmaceutical chemistry, and relates to diaryl-beta-lactam compounds having a structure in a general formula below and having remarkable antitumor activity and application thereof in drug preparation. The invention also comprises application of the compounds, pharmaceutical salts thereof and pharmaceutical compositions thereof in preparation of drugs for preventing or treating tumor-related diseases. The compounds or pharmaceutically acceptable salts thereof provided by the invention can effectively inhibit the growth of nude mouse transplanted tumors in vitro and in vivo through an in-vitro regulation and control mechanism capable of inhibiting the growth of tumor cells by inhibiting tubulin aggregation, and can be used in preparation of drugs for preventing or treating the tumor-related diseases, wherein the tumor-related diseases comprise benign and malignant tumors and other diseases caused by the tumors. The general formula is shown in the specification.
- -
-
Paragraph 0067; 0068; 0069
(2017/10/22)
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- Bioreductively activatable prodrug conjugates of phenstatin designed to target tumor hypoxia
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A variety of solid tumor cancers contain significant regions of hypoxia, which provide unique challenges for targeting by potent anticancer agents. Bioreductively activatable prodrug conjugates (BAPCs) represent a promising strategy for therapeutic intervention. BAPCs are designed to be biologically inert until they come into contact with low oxygen tension, at which point reductase enzyme mediated cleavage releases the parent anticancer agent in a tumor-specific manner. Phenstatin is a potent inhibitor of tubulin polymerization, mimicking the chemical structure and biological activity of the natural product combretastatin A-4. Synthetic approaches have been established for nitrobenzyl, nitroimidazole, nitrofuranyl, and nitrothienyl prodrugs of phenstatin incorporating nor-methyl, mono-methyl, and gem-dimethyl variants of the attached nitro compounds. A series of BAPCs based on phenstatin have been prepared by chemical synthesis and evaluated against the tubulin-microtubule protein system. In a preliminary study using anaerobic conditions, the gem-dimethyl nitrothiophene and gem-dimethyl nitrofuran analogues were shown to undergo efficient enzymatic cleavage in the presence of NADPH cytochrome P450 oxidoreductase. Each of the eleven BAPCs evaluated in this study demonstrated significantly reduced inhibitory activity against tubulin in comparison to the parent anti-cancer agent phenstatin (IC50?=?1.0?μM). In fact, the majority of the BAPCs (seven of the eleven analogues) were not inhibitors of tubulin polymerization (IC50?>?20?μM), which represents an anticipated (and desirable) attribute for these prodrugs, since they are intended to be biologically inactive prior to enzyme-mediated cleavage to release phenstatin.
- Winn, Blake A.,Shi, Zhe,Carlson, Graham J.,Wang, Yifan,Nguyen, Benson L.,Kelly, Evan M.,Ross, R. David,Hamel, Ernest,Chaplin, David J.,Trawick, Mary L.,Pinney, Kevin G.
-
supporting information
p. 636 - 641
(2017/01/17)
-
- 4-AZAPODOPHYLOTOXINS COMPOUNDS
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The present disclosure relates to 4-azapodophylotoxins compounds, pharmaceutical compositions comprising such compounds, kits, and methods for using such compounds or pharmaceutical compositions.
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Page/Page column 73
(2017/09/15)
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- β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells
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Glucuronidation by uridine 5-diphosphoglucuronosyl transferase enzymes (UGTs) is a cause of intrinsic drug resistance in cancer cells. Glucuronidation of combretastatin A-4 (CA-4) was previously identified as a mechanism of resistance in hepatocellular ca
- Malebari, Azizah M.,Greene, Lisa M.,Nathwani, Seema M.,Fayne, Darren,O'Boyle, Niamh M.,Wang, Shu,Twamley, Brendan,Zisterer, Daniela M.,Meegan, Mary J.
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p. 261 - 285
(2017/03/09)
-
- Design, synthesis, and evaluation of curcumin derivatives as Nrf2 activators and cytoprotectors against oxidative death
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Activation of nuclear factor erythroid-2-related factor 2 (Nrf2) has been proven to be an effective means to prevent the development of cancer, and natural curcumin stands out as a potent Nrf2 activator and cancer chemopreventive agent. In this study, we synthesized a series of curcumin analogs by introducing the geminal dimethyl substituents on the active methylene group to find more potent Nrf2 activators and cytoprotectors against oxidative death. The geminally dimethylated and catechol-type curcumin analog (compound 3) was identified as a promising lead molecule in terms of its increased stability and cytoprotective activity against the tert-butyl hydroperoxide (t-BHP)-induced death of HepG2 cells. Mechanism studies indicate that its cytoprotective effects are mediated by activating the Nrf2 signaling pathway in the Michael acceptor- and catechol-dependent manners. Additionally, we verified by using copper and iron ion chelators that the two metal ion-mediated oxidations of compound 3 to its corresponding electrophilic o-quinone, contribute significantly to its Nrf2-dependent cytoprotection. This work provides an example of successfully designing natural curcumin-directed Nrf2 activators by a stability-increasing and proelectrophilic strategy.
- Tu, Zhi-Shan,Wang, Qi,Sun, Dan-Dan,Dai, Fang,Zhou, Bo
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-
- Platinum(IV) complexes conjugated with phenstatin analogue as inhibitors of microtubule polymerization and reverser of multidrug resistance
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Pt(IV) complexes comprising a phenstatin analogue, as dual-targeting Pt(IV) prodrug, were designed and synthesized. They were found not only to carry the DNA binding platinum warhead into the tumor cells, but also to have a small molecular unit to inhibit tubulin polymerization. In vitro evaluation results revealed that Pt(IV) complexes showed better and more potent activity against the test human cancer cells including cisplatin resistant cell lines than their corresponding Pt(II) counterparts. In addition, the Pt(IV) derivative of cisplatin, complex 10, exhibited highly selective inhibition in human cancer cells and displayed no obvious toxicity to two human normal cell lines, respectively. Mechanism study suggested that complex 10 induced cell-cycle arrest at the G2/M phase and caused apoptotic cell death of human lung cancer NCI-H460 cells through the mitochondrial mediated pathway. Moreover, complex 10 effectively inhibited the tumor growth in the NCI-H460 xenograft model.
- Huang, Xiaochao,Huang, Rizhen,Gou, Shaohua,Wang, Zhimei,Liao, Zhixin,Wang, Hengshan
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p. 4686 - 4700
(2017/10/06)
-
- Identification of human T2R receptors that respond to bitter compounds that elicit the bitter taste in compositions, and the use thereof in assays to identify compounds that inhibit (block) bitter taste in compositions and use thereof
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The present invention relates to the discovery that specific human taste receptors in the T2R taste receptor family respond to particular bitter compounds present in, e.g., coffee. Also, the invention relates to the discovery of specific compounds and compositions containing that function as bitter taste blockers and the use thereof as bitter taste blockers or flavor modulators in, e.g., coffee and coffee flavored foods, beverages and medicaments. Also, the present invention relates to the discovery of a compound that antagonizes numerous different human T2Rs and the use thereof in assays and as a bitter taste blocker in compositions for ingestion by humans and animals.
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Page/Page column 360; 361
(2016/02/26)
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- BITTER TASTE MODIFIERS INCLUDING SUBSTITUTED 1-BENZYL-3-(1-(ISOXAZOL-4-YLMETHYL)-1H-PYRAZOL-4-YL)IMIDAZOLIDINE-2,4-DIONES AND COMPOSITIONS THEREOF
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The present invention includes compounds and compositions known to modify the perception of bitter taste, and combinations of said compositions and compounds with additional compositions, compounds, and products. Exemplary compositions comprise one or more of the following: cooling agents; inactive drug ingredients; active pharmaceutical ingredients; food additives or foodstuffs; flavorants, or flavor enhancers; food or beverage products; bitter compounds; sweeteners; bitterants; sour flavorants; salty flavorants; umami flavorants; plant or animal products; compounds known to be used in pet care products; compounds known to be used in personal care products; compounds known to be used in home products; pharmaceutical preparations; topical preparations; cannabis-derived or cannabis-related products; compounds known to be used in oral care products; beverages; scents, perfumes, or odorants; compounds known to be used in consumer products; silicone compounds; abrasives; surfactants; warming agents; smoking articles; fats, oils, or emulsions; and/or probiotic bacteria or supplements.
- -
-
Paragraph 0557; 0558
(2017/01/19)
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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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- Antineoplastic Agents. 585. Isolation of Bridelia ferruginea Anticancer Podophyllotoxins and Synthesis of 4-Aza-podophyllotoxin Structural Modifications
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Cytotoxic constituents of the terrestrial plant Bridelia ferruginea were isolated using bioactivity-guided fractionation, which revealed the presence of the previously known deoxypodophyllotoxin (1), isopicrodeoxypodophyllotoxin (2), β-peltatin (3), β-pel
- Pettit, George R.,Searcy, Justin D.,Tan, Rui,Cragg, Gordon M.,Melody, Noeleen,Knight, John C.,Chapuis, Jean-Charles
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p. 507 - 518
(2016/04/19)
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- Synthesis of a 2-aryl-3-aroyl indole salt (OXi8007) resembling combretastatin A-4 with application as a vascular disrupting agent
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The natural products colchicine and combretastatin A-4 are potent inhibitors of tubulin assembly, and they have inspired the design and synthesis of a large number of small-molecule, potential anticancer agents. The indole-based molecular scaffold is prom
- Hadimani, Mallinath B.,MacDonough, Matthew T.,Ghatak, Anjan,Strecker, Tracy E.,Lopez, Ramona,Sriram, Madhavi,Nguyen, Benson L.,Hall, John J.,Kessler, Raymond J.,Shirali, Anupama R.,Liu, Li,Garner, Charles M.,Pettit, George R.,Hamel, Ernest,Chaplin, David J.,Mason, Ralph P.,Trawick, Mary Lynn,Pinney, Kevin G.
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p. 1668 - 1678
(2013/10/22)
-
- Molecular docking studies of (1E,3E,5E )-1,6-bis(substituted phenyl)-hexa-1,3,5-triene and 1,4-bis(substituted trans-styryl)benzene analogs as novel tyrosinase inhibitors
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We simulated the docking of the tertiary structure of mushroom tyrosinase with our compounds. From the structure-tyrosinase inhibitory activity relationship, it is notable that compounds 4, 8 and 11 showed similar or better activity rates than kojic acid which was used as a positive control. Compounds 17, 21, and 23 among benzene analogs that possess the same substituent showed significantly lower tyrosinase inhibitory effects. Therefore, we have confirmed that among the compounds showing better tyrosinase inhibitory effects than kojic acid, the compounds with triene analogs have better tyrosinase inhibitory effect than the compounds with benzene analogs. Docking simulation suggested the mechanism of compounds by several key residues which had possible hydrogen bonding interactions. The pharmacophore model underlined the features of active compounds, 4,4′-((1E,3E,5E )-hexa-1,3,5-triene-1,6-diyl)diphenol, 5,5′-((1E,3E,5E )-hexa-1,3,5-triene-1,6-diyl)bis(2-methoxy-phenol), and 5,5′-((1 E,3E,5E )-hexa-1,3,5-triene-1,6-diyl)dibenzene-1,3-diol among triene derivatives which had several hydrogen bond groups on both terminal rings. The soundness of the docking results and the agreement with the pharmacophores suggest that it can be conveniently exploited to design inhibitors with an improved affinity for tyrosinase.
- Ha, Young Mi,Lee, Hye Jin,Park, Daeui,Jeong, Hyoung Oh,Park, Ji Young,Park, Yun Jung,Lee, Kyung Jin,Lee, Ji Yeon,Moon, Hyung Ryong,Chung, Hae Young
-
-
- New phenstatin-fatty acid conjugates: Synthesis and evaluation
-
New phenstatin-fatty acid conjugates have been synthesized and tested against the KB-3-1, H460, MCF-7 and HEK293 cell lines, with an increase in anti-proliferative activity being observed at the micro-molar level paralleling an increase in un-saturation in the fatty acid component.
- Chen, Jinhui,Brown, David P.,Wang, Yi-Jun,Chen, Zhe-Sheng
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supporting information
p. 5119 - 5122
(2013/09/12)
-
- Amidobenzothiazoles And Process For The Preparation Thereof
-
The present invention provides a compound of general formulae A useful as potential anti-cancer agents against human cancer cell lines and a process for the preparation thereof. Where in R, R1, R2═H, alkyl, alkoxy, halo, haloalkyl, halomethoxy, nitro and G= Where in R, R1, R2═H, alkyl, alkoxy, halo, haloalkyl, halomethoxy, nitro and G=
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-
- Increased endothelial cell selectivity of triazole-bridged dihalogenated A-ring analogues of combretastatin A-1
-
The antiproliferative activity on ovarian cancer (SK-OV-3) cells of a series of triazole-bridged combretastatin analogues (37, 38, 40-43) containing dihalogenation of the A-ring is reported, and compared with their trimethoxy analogues (5, 15, 39). It was found that dihalogenation with either bromine or iodine was a tolerated modification when compared to the parent compound combretastatin (CA-4, 1) and had less effect than B-ring modification on potency. These compounds exhibited G2/M arrest, and maintained antitubulin activity. Further assays on human umbilical vein endothelial cells (HUVECs) demonstrated the potential antivascular effects of these triazoles. Of particular note was a 3,5-diiodo-4-methoxyaryl triazole (43) which had promising 7-fold selectivity for HUVECs over ovarian cancer cells.
- Beale, Thomas M.,Bond, Peter J.,Brenton, James D.,Charnock-Jones, D. Stephen,Ley, Steven V.,Myers, Rebecca M.
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experimental part
p. 1749 - 1759
(2012/04/10)
-
- A-ring dihalogenation increases the cellular activity of combretastatin-templated tetrazoles
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The combretastatins have been investigated for their antimitotic and antivascular properties, and it is widely postulated that a 3,4,5-trimethoxyaryl A-ring is essential to maintain potent activity. We have synthesized new tetrazole analogues (32a€"34), demonstrating that 3,5-dihalogenation can consistently increase potency by up to 5-fold when compared to the equivalent trimethoxy compound on human umbilical vein endothelial cells (HUVECs) and a range of cancer cells. Moreover, this increased potency offsets that lost by installing the tetrazole bridge into combretastatin A-4 (1), giving crystalline, soluble compounds that have low nanomolar activity, arrest cells in G2/M phase, and retain microtubule inhibitory activity. Molecular modeling has shown that optimized packing within the binding site resulting in increased Coulombic interaction may be responsible for this improved activity.
- Beale, Thomas M.,Allwood, Daniel M.,Bender, Andreas,Bond, Peter J.,Brenton, James D.,Charnock-Jones, D. Stephen,Ley, Steven V.,Myers, Rebecca M.,Shearman, James W.,Temple, Jill,Unger, Jessica,Watts, Ciorsdaidh A.,Xian, Jian
-
scheme or table
p. 177 - 181
(2012/05/05)
-
- First total synthesis of two new heterocyclic compounds: Bretschneiderazines A and B
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Facile synthesis of the two new natural heterocyclic compounds bretschneiderazines A (2) and B (3), isolated from an extract of the stems of Bretschneidera sinensis, is reported. We employed the cyclization reaction of benzamide by directed lithiation and
- Liu, Qing Chao,Guo, Tian Tian,Fan, Zheng,Li, Dong,Li, Wen Hong
-
scheme or table
p. 801 - 803
(2012/01/05)
-
- Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones
-
A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC50 values of 7 nM and 10 nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC50 = 1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.
- O'Boyle, Niamh M.,Greene, Lisa M.,Bergin, Orla,Fichet, Jean-Baptiste,McCabe, Thomas,Lloyd, David G.,Zisterer, Daniela M.,Meegan, Mary J.
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experimental part
p. 2306 - 2325
(2011/05/12)
-
- Anticancer effects of the metabolic products of the resveratrol analogue, DMU-212: Structural requirements for potency
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The methoxylated trans-stilbene resveratrol analogue, (E)-3,4,5,4′- tetramethoxystilbene (1), has shown promising antiproliferative activity in in vitro cell line and in vivo models. In vivo 1 gives rise to several metabolic products through demethylation or hydroxylation reactions at the stilbene moiety. In the present study we examined the anticancer activity of 1 and the metabolites (E)-3′-hydroxy-3,4,5,4′-tetramethoxystilbene (2), (E)-4′-hydroxy-3,4,5-trimethoxystilbene (3), (E)-4-hydroxy-3,5,4′- trimethoxystilbene (4) and (E)-3-hydroxy-4,5,4′-trimethoxystilbene (5) by means of cell viability testing, cell cycle analysis, immunostaining and Western blotting. Compounds 1 and 2 exhibited submicromolar toxicity in MCF-7 breast adenocarcinoma and HepG2 hepatoma cells, whereas 3, 4 and 5 were inactive in terms of inhibition of cellular proliferation. Incubation with 1 or 2 at 10 μM for 24 h induced apoptosis and G2/M cell cycle arrest in MCF-7 and HepG2 cells. Immunostaining of MCF-7 cells for β-tubulin in the presence of either 1 or 2 revealed shorter localization of the protein around the nucleus, as compared to control cells. Western blot analyses further demonstrated that treatment with either 1 or 2 at concentrations between 30 and 50 μM for 24 h caused a downregulation in the levels of β-tubulin and cyclin D1 expression and an upregulation in the levels of p53 expression in MCF-7 and HepG2 cells. 2 further increased the ratio of mRNA levels of the apoptosis-related genes Bax/Bcl-xL in both MCF-7 and HepG2 cells in a dose-dependent manner. We conclude that 2 inhibits HepG2 and MCF-7 cellular proliferation by inducing apoptosis and G2/M arrest through p53 and Bax/Bcl-xL upregulation. Our findings further demonstrate that trimethoxy substitutions along with the presence of a methoxy group at position 4′ are necessary for retaining the activity of 1.
- Androutsopoulos, Vasilis P.,Ruparelia, Ketan C.,Papakyriakou, Athanasios,Filippakis, Harilaos,Tsatsakis, Aristeidis M.,Spandidos, Demetrios A.
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experimental part
p. 2586 - 2595
(2011/06/21)
-
- An efficient synthetic strategy for obtaining 4-methoxy carbon isotope labeled combretastatin a-4 phosphate and other Z-combretastatins
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Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [11C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable
- Pettit, George R.,Minardi, Mathew D.,Hogan, Fiona,Price, Pat M.
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experimental part
p. 399 - 403
(2010/08/05)
-
- PROCESSES FOR PREPARING (E)-STYRYLBENZYLSULFONE COMPOUNDS AND USES THEREOF FOR TREATING PROLIFERATIVE DISORDERS
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Processes for preparing (E)-2,4,6-(Trimethoxystyryl)-3-O-Phosphate Disodium-4-Methoxybenzyl Sulfones and uses thereof as antiproliferative agents, including, for example, anticancer agents, and as radioprotective and chemoprotective agents.
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-
Page/Page column 28
(2010/06/22)
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- 1,2,3-Triazole analogs of combretastatin A-4 as potential microtubule-binding agents
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A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2, 3-triazol-1-yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)- 1H-1,2,3-triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore.
- Odlo, Kristin,Fournier-Dit-Chabert, Jérémie,Ducki, Sylvie,Gani, Osman A.B.S.M.,Sylte, Ingebrigt,Hansen, Trond Vidar
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scheme or table
p. 6874 - 6885
(2010/10/19)
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- Synthesis and evaluation of azetidinone analogues of combretastatin A-4 as tubulin targeting agents
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The synthesis and antiproliferative activity of a new series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization, and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41, and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent antiproliferative activity of the series. β-Lactam 41 in particular showed subnanomolar activity in MCF-7 breast cancer cells (IC50 = 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumor agents that target tubulin.
- O'Boyle, Niamh M.,Carr, Miriam,Greene, Lisa M.,Bergin, Orla,Nathwani, Seema M.,McCabe, Thomas,Lloyd, David G.,Zisterer, Daniela M,Meegan, Mary J.
-
supporting information; experimental part
p. 8569 - 8584
(2011/02/28)
-
- 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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- Application of the McMurry coupling reaction in the synthesis of tri- and tetra-arylethylene analogues as potential cancer chemotherapeutic agents
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Structural redesign of selected non-steroidal estrogen receptor binding compounds has previously been successful in the discovery of new inhibitors of tubulin assembly. Accordingly, tetra-substituted alkene analogues (21-30) were designed based in part on combinations of the structural and electronic components of tamoxifen and combretastatin A-4 (CA4). The McMurry coupling reaction was used as the key synthetic step in the preparation of these tri- and tetra-arylethylene analogues. The structural assignment of E, Z isomers was determined on the basis of 2D-NOESY experiments. The ability of these compounds to inhibit tubulin polymerization and cell growth in selected human cancer cell lines was evaluated. Although the compounds were found to be less potent than CA4, these analogues significantly advance the known structure-activity relationship associated with the colchicine binding site on β-tubulin.
- Tanpure, Rajendra P.,Harkrider, Amanda R.,Strecker, Tracy E.,Hamel, Ernest,Trawick, Mary Lynn,Pinney, Kevin G.
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supporting information; experimental part
p. 6993 - 7001
(2009/12/24)
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- Isocombretastatins A: 1,1-Diarylethenes as potent inhibitors of tubulin polymerization and cytotoxic compounds
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Isocombretastatins A are 1,1-diarylethene isomers of combretastatins A. We have synthesized the isomers of combretastatin A-4, deoxycombretastatin A-4, 3-amino-deoxycombretastatin A-4 (AVE-8063), naphthylcombretastatin and the N-methyl- and N-ethyl-5-indo
- Alvarez, Raquel,Alvarez, Concepcion,Mollinedo, Faustino,Sierra, Beatriz G.,Medarde, Manuel,Pelaez, Rafael
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scheme or table
p. 6422 - 6431
(2011/02/24)
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- Z-stilbenes derivatives and the pharmaceutical composition thereof
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A series of Z-stilbenes derivatives are disclosed, which have the structure as shown by formula 1. In the structure of formula 1, X is hydrogen, NHR, or nitro group, and R is hydrogen. Y and Z is independently hydrogen, halogen, C1-C10 /s
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Page/Page column 5
(2008/06/13)
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- Design, synthesis, and biological evaluation of (E)-styrylbenzylsulfones as novel anticancer agents
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Cell cycle progression is regulated by cyclins and cyclin-dependent kinases, which are formed at specific stages of the cell cycle and regulate the G1/S and G2/M phase transitions, employing a series of "checkpoints" governed by phosphorylation of their substrates. Tumor development is associated with the loss of these checkpoint controls, and this provides an approach for the development of therapeutic agents that can specifically target tumor cells. Here, we describe the synthesis and SAR of a novel group of cytotoxic molecules that selectively induce growth arrest of normal cells in the G1 phase while inducing a mitotic arrest of tumor cells resulting in selective killing of tumor cell populations with little or no effect on normal cell viability. The broad spectrum of antitumor activity in vitro and xenograft models, lack of in vivo toxicity, and drug resistance suggest potential for use of these agents in cancer therapy.
- Reddy, M. V. Ramana,Mallireddigari, Muralidhar R.,Cosenza, Stephen C.,Pallela, Venkat R.,Iqbal, Nabisa M.,Robell, Kimberly A.,Kang, Anthony D.,Reddy, E. Premkumar
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- Total synthesis of ovalifoliolatin B, acerogenins A and C
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A short and concise route for the synthesis of ovalifoliolatin B, a highly strained macrocyclic diaryl ether heptanoid natural product that also provides quick access to acerogenins A and C natural products has been reported.
- Kishore Kumar,Natarajan, Amarnath
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p. 2103 - 2105
(2008/09/18)
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- Synthesis and biological activity of fluorinated combretastatin analogues
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With the aim of understanding the influence of fluorine on the double bond of the cis-stilbene moiety of combretastatin derivatives and encouraged by a preliminary molecular modeling study showing a different biological environment on the interaction site
- Alloatti, Domenico,Giannini, Giuseppe,Cabri, Walter,Lustrati, Isabella,Marzi, Mauro,Ciacci, Andrea,Gallo, Grazia,Tinti, M. Ornella,Marcellini, Marcella,Riccioni, Teresa,Guglielmi, Mario B.,Carminati, Paolo,Pisano, Claudio
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p. 2708 - 2721
(2008/12/22)
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- ACTIVATED CYTOTOXIC COMPOUNDS FOR ATTACHMENT TO TARGETING MOLECULES FOR THE TREATMENT OF MAMMALIAN DISEASE CONDITIONS
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Activated cytotoxic compounds are described for attachment to targeting molecules for the treatment of a mammalian disease condition which comprise, an activator, a spacer linker, a linker (e.g., self-immolative), and a cytotoxic drug selected from the group consisting of AMINO-SUBSTITUTED (E)-2,6-DIALKOXYSTYRYL 4-SUBSTITUTED BENZYLSULFONES, AMINO-AND- HYDROXY SUBSTITUTED STYRYLSULFONANILIDES, and SUBSTITUTED PHENOXY- AND PHENYLTHIO-STYRYLSULFONE DERIVATIVES. Activated cytotoxic compound attached to a targeting molecule are described wherein the targeting molecule is selected from the group consisting essentially of an antibody, a receptor, a ligand, a cytokine, a hormone, and a signal transduction molecule. The invention is further directed to a method of treatment of disease conditions.
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Page/Page column 55
(2010/11/30)
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- Substituted Phenoxy-and Phenylthio-Derivatives for Treating Proliferative Disorders
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Substituted phenol derivatives of Formula (I) are useful as antiproliferative agents including, for example, anticancer agents, and as radioprotective and chemoprotective agents.
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Page/Page column 45
(2010/11/30)
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- Novel pyridinyl and pyrimidinylcarbazole sulfonamides as antiproliferative agents
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A series of azaheterocyclic carbazole sulfonamides was synthesized and evaluated for antiproliferative activity. The most potent compounds N-(2,6-dimethoxypyridine-3-yl)-9-ethyl and 9-methylcarbazole-3-sulfonamide (13 and 14) gave significant cytotoxicity (IC50 = 122 and 101 nM). Compound 13 displayed submicromolar activities against seven human tumor cell lines. The SARs of this series of sulfonamides which includes the influence of azaheterocycle rings, sulfonamide linkage, and the carbazole ring are described.
- Hu, Laixing,Li, Zhuo-rong,Wang, Yue-ming,Wu, Yanbin,Jiang, Jian-Dong,Boykin, David W.
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p. 1193 - 1196
(2008/01/27)
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- Quinone reductase induction activity of methoxylated analogues of resveratrol
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Agents that induce the activity of phase II enzymes play an important role in intervening with the carcinogenic process at the initiation stage. Resveratrol is well known for its chemopreventive activity against major stages of carcinogenesis. In this study, several methoxylated analogues of resveratrol were synthesized and evaluated for their ability to induce the activity of the phase II enzyme quinone reductase (QR). Methoxy groups serve to increase lipophilicity and improve metabolic stability. Compared to resveratrol, analogues with ortho-methoxy substituents were found to be more potent inducers of QR and to exert their activity in a qualitatively different manner. The greater induction activities associated with these stilbenoids serve as a useful starting point for the design of improved chemopreventive agents.
- Zhang,Go
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p. 841 - 850
(2008/02/12)
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- The kulinkovich reaction in the synthesis of constrained N,N-dialkyl neurotransmitter analogues
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An intermolecular Ti(IV)-mediated cyclopropanation reaction has been used to synthesize substituted 2-phenylcyclopropylamines and constrained analogues of the neurotransmitters histamine and tryptamine. Many hydroxy- and methoxy-substituted phenylcyclopropylamines are known to inhibit monoamine oxidase and have been shown to mimic hallucinogens. These compounds were made in 1 to 5 steps from readily available starting materials.
- Faler, Catherine A.,Joullie, Madeleine M.
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p. 1987 - 1990
(2008/02/02)
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- N-Phenyl-N′-(2-chloroethyl)urea analogues of combretastatin A-4: Is the N-phenyl-N′-(2-chloroethyl)urea pharmacophore mimicking the trimethoxy phenyl moiety?
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A series of novel N-phenyl-N′-(2-chloroethyl)urea derivatives potentially mimicking the structure of combretastatin A-4 were synthesized and tested for their cell growth inhibition and their binding to the colchicine-binding site of β-tubulin. Compounds 2a, 3a, and 3b were found to inhibit cell growth at the micromolar level on four human tumor cell lines. Flow cytometric analysis indicates that the new compounds act as antimitotics and arrest the cell cycle in G2/M phase. Covalent binding of 2a, 3a, and 3b to the colchicine-binding site of β-tubulin was confirmed also using SDS-PAGE and competition assays.
- Fortin, Sebastien,Moreau, Emmanuel,Lacroix, Jacques,Teulade, Jean-Claude,Patenaude, Alexandre,C-Gaudreault, Rene
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p. 2000 - 2004
(2008/02/04)
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- Synthesis of radiolabeled stilbene derivatives as new potential PET probes for aryl hydrocarbon receptor in cancers
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New carbon-11 and fluorine-18 labeled stilbene derivatives, cis-3,5-dimethoxy-4′-[11C]methoxystilbene (4′-[11C]8a), cis-3,4′,5-trimethoxy-3′-[11C]methoxystilbene (3′-[11C]8b), trans-3,5-dimethoxy-4′-[11C]methoxystilbene (4′-[11C]10a), trans-3,4′,5-trimethoxy-3′-[11C]methoxystilbene (3′-[11C]10b), cis-3,5-dimethoxy-4′-[18F]fluorostilbene (4′-[18F]12a), and trans-3,5-dimethoxy-4′-[18F]fluorostilbene (4′-[18F]13a), were designed and synthesized as potential PET probes for aryl hydrocarbon receptor (AhR) in cancers.
- Gao, Mingzhang,Wang, Min,Miller, Kathy D.,Sledge, George W.,Hutchins, Gary D.,Zheng, Qi-Huang
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p. 5767 - 5772
(2007/10/03)
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- 2-Amino and 2′-aminocombretastatin derivatives as potent antimitotic agents
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A novel series of 2-amino and 2′-aminocombretastatin derivatives were synthesized and evaluated for antitumor activity. Several compounds had excellent antiproliferative activity as inhibitors of tubulin polymerization. Compounds 11, 20, and 21 with ICsu
- Chang, Jang-Yang,Yang, Ming-Fang,Chang, Chi-Yen,Chen, Chi-Ming,Kuo, Ching-Chuan,Liou, Jing-Ping
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p. 6412 - 6415
(2007/10/03)
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- Synthesis and structure-activity relationship studies of 1,3-diarylprop-2-yn-1-ones: Dual inhibitors of cyclooxygenases and lipoxygenases
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A group of 1,3-diarylprop-2-yn-1-ones (13, 17, 23, 26 and 27) possessing a C-3 p-SO2Me COX-2 pharmacophore were designed, synthesized and evaluated as potential dual inhibitors of cyclooxygenase-1/2 (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) t
- Rao, P. N. Praveen,Chen, Qiao-Hong,Knaus, Edward E.
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p. 1668 - 1683
(2007/10/03)
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- COMPOSITION AND METHODS FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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Methods and compositions are provided for treating proliferative disorders, wherein the composition comprises at least one compound according to Formula (I), wherein R1 is selected from the group consisting of -OH, -NH2, -NH-CH2
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Page/Page column 35
(2010/11/24)
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- FLUOROCOMBRETASTATIN AND DERIVATIVES THEREOF
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The present invention is related to new derivatives of Combretastatin, of Formula (I) obtained by total synthesis. The strategy developed for each of the compounds is to i) replace a halogen (i.e. fluorine atom) to hydrogen on olefinic bound; ii) replace
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Page/Page column 10
(2008/06/13)
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- Synthesis and biological evaluation of 1,3-diphenylprop-2-yn-1-ones as dual inhibitors of cyclooxygenases and lipoxygenases
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A new class of 1,3-diphenylprop-2-yn-1-ones possessing a p-MeSO2 COX-2 phamacophore on the C-3 phenyl ring was designed for evaluation as dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX). Among the group of compounds evaluated, 1-
- Rao, P.N. Praveen,Chen, Qiao-Hong,Knaus, Edward E.
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p. 4842 - 4845
(2007/10/03)
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- INDOLE-CONTAINING COMPOUNDS WITH ANTI-TUBULIN AND VASCULAR TARGETING ACTIVITY
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Trimethoxyphenyl substituted indole ligands have been discovered which demonstrate impressive cytotoxicity as well as a remarkable ability to inhibit tubulin assembly. Such compounds as well as related derivatives are excellent clinical candidates for the
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- 1,3-Dipolar cycloaddition route to novel isoxazole-type derivatives related to combretastatin A-4
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A series of compounds related to combretastatin A-4, containing a five-membered heterocyclic ring interposed between the two phenyl groups have been prepared. Synthetic approach involves 1,3-dipolar cycloaddition of various 3,4,5-trimethoxyphenyl units with an in situ generated nitrile oxide from a suitable aldoxime using sodium hypochlorite. Depending on the nature of the dipolarophile, 3,5-diarylisoxazole derivatives were obtained along with the 3,4-regioisomeric isomers.
- Kaffy, Julia,Monneret, Claude,Mailliet, Patrick,Commer?on, Alain,Pontikis, Renée
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p. 3359 - 3362
(2007/10/03)
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