- Design, synthesis of phenstatin/isocombretastatin-oxindole conjugates as antimitotic agents
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A series of phenstatin/isocombretastatin-oxindole conjugates was synthesized and tested for their cytotoxic activity against five human cancer cells such as prostate (DU-145), lung (A549), colon (HT-29), breast (MCF-7), liver (HepG2) cancer cells with IC50 values ranging from 0.049 to 38.90 μM. Amongst them, two conjugates (5c and 5d) showed broad spectrum of antiproliferative efficacy on lung cancer cells with an IC50 value of 79 nM and 93 nM, respectively, whereas on colon cancer cells with an IC50 values 45 nM and 49 nM, respectively. In addition, cell cycle assay revealed that these conjugates (5c and 5d) arrest at the G2/M phase and leads to apoptotic cell death which was confirmed by Annexin V-FITC and mitochondrial membrane depolarization. Further, the tubulin polymerization assay analysis results suggest that these conjugates particularly 5c and 5d exhibit significant inhibitory effect on the tubulin assembly with an IC50 value of 1.23 μM and 1.01 μM, respectively. Molecular docking studies indicated that these compounds (5c and 5d) occupy the colchicine binding site of the tubulin.
- Kumar, G. Bharath,Nayak, V. Lakshma,Sayeed, Ibrahim Bin,Reddy, Vangala Santhosh,Shaik, Anver Basha,Mahesh, Rasala,Baig, Mirza Feroz,Shareef, Mohd Adil,Ravikumar,Kamal, Ahmed
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- Synthesis of phenstatin/isocombretastatin-chalcone conjugates as potent tubulin polymerization inhibitors and mitochondrial apoptotic inducers
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A series of phenstatin/isocombretastatin-chalcones were synthesized and screened for their cytotoxic activity against various human cancer cell lines. Some representative compounds exhibited significant antiproliferative activity against a panel of sixty human cancer cell lines of the NCI, with GI50 values in the range of 0.11 to 19.0 μM. Three compounds (3b, 3c and 3e) showed a broad spectrum of antiproliferative efficacy on most of the cell lines in the sub-micromolar range. In addition, all the synthesized compounds (3a-l and 4a-l) displayed moderate to excellent cytotoxicity against breast cancer cells such as MCF-7 and MDA-MB-231 with IC50 values in the range of 0.5 to 19.9 μM. Moreover, the tubulin polymerization assay and immunofluorescence analysis results suggest that some of these compounds like 3c and 3e exhibited significant inhibitory effect on the tubulin assembly with an IC50 value of 0.8 μM and 0.6 μM respectively. A competitive binding assay suggested that these compounds bind at the colchicine-binding site of tubulin. A cell cycle assay revealed that these compounds arrest at the G2/M phase and lead to apoptotic cell death. Furthermore, this was confirmed by Hoechst 33258 staining, activation of caspase 9, DNA fragmentation, Annexin V-FITC and mitochondrial membrane depolarization. Molecular docking studies indicated that compounds like 3e occupy the colchicine binding site of tubulin. This journal is
- Kamal, Ahmed,Kumar, G. Bharath,Vishnuvardhan,Shaik, Anver Basha,Reddy, Vangala Santhosh,Mahesh, Rasala,Sayeeda, Ibrahim Bin,Kapure, Jeevak Sopanrao
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- Late-Stage Heteroarylation of Hetero(aryl)sulfonium Salts Activated by α-Amino Alkyl Radicals
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We report a late-stage heteroarylation of aryl sulfonium salts through activation with α-amino alkyl radicals in a mechanistically distinct approach from previously reported halogen-atom transfer (XAT). The new mode of activation of aryl sulfonium salts p
- Alvarez, Eva Maria,Berger, Florian,Karl, Teresa,Ritter, Tobias,Torkowski, Luca
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p. 13609 - 13613
(2021/05/06)
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- Discovery of 5-(2′,4′-difluorophenyl)-salicylanilides as new inhibitors of receptor activator of NF-κ°B ligand (RANKL)-induced osteoclastogenesis
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To improve the inhibitory potency of lead compound NDMC101 on RANKL-induced osteoclastogenesis, a series of new 5-(2′,4′-difluorophenyl)-salicylanilide derivatives were synthesized and evaluated for osteoclast inhibition by using TRAP-staining assay. Among them, both of compounds 6d and 6i showed three-fold increase in osteoclast-inhibitory activities compared to NDMC101 at half-inhibitory concentration. Further, the mechanistic study showed that 6d and 6i could suppress RANKL-induced osteoclastogenesis-related genes, such as NFATc1, c-fos, TRAP, and cathepsin K. Their inhibitory activities were further confirmed by including specific inhibition of NF-κ°B and NFATc1 expression levels in nucleus. In addition, 6d and 6i also could significantly attenuate bone-resorbing activity of osteoclasts by performing pit formation assay. Thus, a new class of 5-(2′,4′-difluorophenyl)-salicylanilide derivatives may be considered as essential lead structures for the further development of anti-resorptive agents.
- Lee, Chia-Chung,Liu, Fei-Lan,Chen, Chun-Liang,Chen, Tsung-Chih,Chang, Deh-Ming,Huang, Hsu-Shan
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p. 115 - 126
(2015/06/02)
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- Copper-catalyzed formal c-h carboxylation of aromatic compounds with carbon dioxide through arylaluminum intermediates
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The C-H bond carboxylation of various aromatic compounds with CO2 was achieved by the deprotonative alumination with a mixed alkyl amido lithium aluminate compound iBu3Al(TMP)Li followed by the NHC-copper-catalyzed carboxylation of the resulting arylaluminum species, which afforded the corresponding carboxylation products in high yield and high selectivity. In addition to benzene derivatives, heteroarenes such as benzofuran, benzothiophene, and indole derivatives are also suitable substrates. Functional groups such as Cl, Br, I, vinyl, amide, and CN could survive the reaction conditions. Some key reaction intermediates such as the copper aryl and isobutyl complexes and their carboxylation products were isolated and structurally characterized by X-ray crystallographic analyses, thus offering important information on the reaction mechanism.
- Ueno, Atsushi,Takimoto, Masanori,Wylie,Nishiura, Masayoshi,Ikariya, Takao,Hou, Zhaomin
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supporting information
p. 1010 - 1016
(2015/03/31)
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- Gold(I)-catalyzed iodination of arenes
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A wide variety of electron-rich arenes were efficiently converted into the corresponding iodinated compounds via a gold(I)-catalyzed reaction under mild conditions. Georg Thieme Verlag Stuttgart. New York.
- Leboeuf, David,Ciesielski, Jennifer,Frontier, Alison J.
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supporting information
p. 399 - 402
(2014/03/21)
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- Synthesis and structure-activity relationship studies of conformationally flexible tetrahydroisoquinolinyl triazole carboxamide and triazole substituted benzamide analogues as σ2 receptor ligands
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Two novel classes of compounds targeting the sigma-2 (σ2) receptor were synthesized, and their bioactivities to binding σ1 and σ2 receptors were measured. Four novel triazole carboxamide analogues, 24d, 24e, 24f, and 39c, demonstrated high affinity and selectivity for the σ2 receptor. These data suggest 11C-labeled versions of these compounds may be potential σ2-selective radiotracers for imaging the proliferative status of solid tumors.
- Bai, Suping,Li, Shihong,Xu, Jinbin,Peng, Xin,Sai, Kiran,Chu, Wenhua,Tu, Zhude,Zeng, Chenbo,Mach, Robert H.
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supporting information
p. 4239 - 4251
(2014/06/09)
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- Experimental and theoretical study of Hoveyda-Grubbs catalysts modified by perfluorohexyl ponytail in the alkoxybenzylidene ligand
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The alkoxybenzylidene ligand of Hoveyda-Grubbs 1st and 2nd generation catalysts was modified with one or two perfluorohexyl groups by Ullmann reaction with the aim to improve both the fluorophilicity and activity of the catalyst. While bis(perfluorohexyla
- Kví?ala, Jaroslav,Schindler, Martin,Kelbichová, Vendula,Babuněk, Mario,Rybá?ková, Markéta,Kví?alová, Magdalena,Cva?ka, Josef,B?ezinová, Anna
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- Structure-based optimization and biological evaluation of human 20α-hydroxysteroid dehydrogenase (AKR1C1) salicylic acid-based inhibitors
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The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (Ki = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3α-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC50 value equal to 100 nM.
- El-Kabbani, Ossama,Scammells, Peter J.,Day, Tom,Dhagat, Urmi,Endo, Satoshi,Matsunaga, Toshiyuki,Soda, Midori,Hara, Akira
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experimental part
p. 5309 - 5317
(2011/01/04)
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- Gold-catalyzed halogenation of aromatics by N-halosuccinimides
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(Chemical Equation Presented) Golden bromination: A highly efficient and mild AuCl3-catalyzed bromination of aromatic rings with Nbromosuccinimide (NBS) has been developed. This method works with a low catalyst loading (down to 0.01 mol %) and can be combined with transition metal catalyzed transformations to deliver various aryl products.
- Mo, Fanyang,Yan, Jerry Mingtao,Qiu, Di,Li, Fei,Zhang, Yan,Wang, Jianbo
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supporting information; scheme or table
p. 2028 - 2032
(2010/06/17)
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- Synthesis of 5-ortho-carboranylsalicylaldehyde and an indolinospirobenzopyran
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5-ortho-Carboranylsalicylaldehyde was prepared from 5-iodosalicylaldehyde in six steps in 18% overall yield, and also from 5-iodosalicylic acid in seven steps in 45% overall yield. The reaction of 5-ortho-carboranylsalicylaldehyde with Fischer's base gave
- Lee, Seung Hwan,Kwon, Young Bum,Yoon, Cheol Min
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experimental part
p. 4069 - 4078
(2009/12/24)
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- Self-assembly of vesicles from the stacking of a dipodal F?H-N hydrogen bonded arylamide foldamer
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In this paper, we report the synthesis and self-assembling behavior of an F?H-N hydrogen bonding-induced arylamide-based dipodal foldamer. SEM, AFM, TEM, and XRD studies reveal that this preorganized oligomer stacks to form vesicles in methanol-chloroform
- Wang, Lu,Xiao, Ze-Yun,Hou, Jun-Li,Wang, Gui-Tao,Jiang, Xi-Kui,Li, Zhan-Ting
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experimental part
p. 10544 - 10551
(2010/02/27)
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- Synthesis and biological evaluation of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: Dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory ac
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A novel class of salicylic acid and N-acetyl-2-carboxybenzenesulfonamide regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to its C-4 or C-5 position was designed for evaluation as anti-inflammatory (AI) agents. Repl
- Chowdhury, Morshed A.,Abdellatif, Khaled R.A.,Dong, Ying,Das, Dipankar,Yu, Gang,Velazquez, Carlos A.,Suresh, Mavanur R.,Knaus, Edward E.
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experimental part
p. 6855 - 6861
(2010/05/19)
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- Alkenyldiarylmethanes, Fused Analogs And Syntheses Thereof
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Non-nucleoside inhibitors of HIV-1 reverse transcriptase are described. Such inhibitors may be used as part of a combination therapy to treat HIV infection. Compounds described herein exhibit antiviral potency. In addition, compounds described herein exhibit metabolic stability. Also described herein are processes for preparing Non-nucleoside inhibitors of HIV-1 reverse transcriptase.
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Page/Page column 24; 11
(2009/01/20)
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- BIS-ARYL KINASE INHIBITORS AND METHOD
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Selected compounds are effective for prophylaxis and treatment of diseases, such as HGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
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Page/Page column 43
(2010/11/25)
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- The enantioselective Birch-Cope sequence for the synthesis of carbocyclic quaternary stereocenters. Application to the synthesis of (+)-mesembrine
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A synthetic technique for generating carbocyclic quaternary stereocenters with exceptionally high levels of enantioselectivity is described. A sequence of three reactions, enantioselective Birch reduction-allylation, enol ether hydrolysis, and Cope rearrangement, is used to stereoselectively generate chiral quaternary centers on a 2-cyclohexen-1-one ring. The products of the sequence are 4,4-disubstituted-2-carboxamide-2-cyclohexen-1-one structures which are versatile intermediates in complex natural product synthesis. An application of the sequence to the synthesis of (+)-mesembrine illustrates the utility of these intermediates.
- Paul, Tapas,Malachowski, William P.,Lee, Jisun
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p. 4007 - 4010
(2007/10/03)
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- Synthesis, anti-HIV activity, and metabolic stability of new alkenyldiarylmethane HIV-1 non-nucleoside reverse transcriptase inhibitors
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Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, 18 novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-cyanophenyl, or 3-fluoro-5- trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.
- Deng, Bo-Liang,Hartman, Tracy L.,Buckheit Jr., Robert W.,Pannecouque, Christophe,De Clercq, Erik,Fanwick, Phillip E.,Cushman, Mark
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p. 6140 - 6155
(2007/10/03)
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- Diflunisal Analogues Stabilize the Native State of Transthyretin. Potent Inhibition of Amyloidogenesis
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Analogues of diflunisal, an FDA-approved nonsteroidal antiinflammatory drug (NSAID), were synthesized and evaluated as inhibitors of transthyretin (TTR) aggregation, including amyloid fibril formation. High inhibitory activity was observed for 26 of the compounds. Of those, eight exhibited excellent binding selectivity for TTR in human plasma (binding stoichiometry > 0.50, with a theoretical maximum of 2.0 inhibitors bound per TTR tetramer). Biophysical studies reveal that these eight inhibitors dramatically slow tetramer dissociation (the rate-determining step of amyloidogenesis) over a duration of 168 h. This appears to be achieved through ground-state stabilization, which raises the kinetic barrier for tetramer dissociation. Kinetic stabilization of WT TTR by these eight inhibitors is further substantiated by the decreasing rate of amyloid fibril formation as a function of increasing inhibitor concentration (pH 4.4). X-ray cocrystal structures of the TTR·182 and TTR·202 complexes reveal that 18 and 20 bind in opposite orientations in the TTR binding site. Moving the fluorines from the meta positions in 18 to the ortho positions in 20 reverses the binding orientation, allowing the hydrophilic aromatic ring of 20 to orient in the outer binding pocket where the carboxylate engages in favorable electrostatic interactions with the ε-ammonium groups of Lys 15 and 15′. The hydrophilic aryl ring of 18 occupies the inner binding pocket, with the carboxylate positioned to hydrogen bond to the serine 117 and 117′ residues. Diflunisal itself appears to occupy both orientations based on the electron density in the TTR·12 structure. Structure-activity relationships reveal that para-carboxylate substitution on the hydrophilic ring and dihalogen substitution on the hydrophobic ring afford the most active TTR amyloid inhibitors.
- Adamski-Werner, Sara L.,Palaninathan, Satheesh K.,Sacchettini, James C.,Kelly, Jeffery W.
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p. 355 - 374
(2007/10/03)
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- Novel fragmentation reaction of 2-alkyl- and 2,4-dialkyl-3-iodo-1- oxocyclohexan-2,4-carbolactones
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2-Alkyl- and 2,4-dialkyl-3-iodo-1-oxocyclohexan-2,4-carbolactones undergo lithium hydroxide- and lithium alkoxide-induced fragmentation reactions to provide butenolides, γ-hydroxycyclohexenones, and/or γ- butyrolactones. In general, product distribution is governed by two factors: (1) the nature of nucleophiles and (2) the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanones. Lithium hydroxide-induced fragmentation provides butenolides and γ-hydroxycyclohexenones. In contrast, lithium alkoxide-promoted fragmentation results in predominantly 5-substituted γ-butyrolactones along with a small amount of butenolides in limited cases. Fragmentation products induced by lithium hydroxide are largely influenced by the steric bulkiness of the substituents at C-2 and C-4 of the cyclohexanone ring. The bulky substituents render the exclusive formation of butenolides.
- Khim, Seock-Kyu,Dai, Mingshi,Zhang, Xuqing,Chen, Lei,Pettus, Liping,Thakkar, Kshitij,Schultz, Arthur G.
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p. 7728 - 7733
(2007/10/03)
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- Melanocortin-4 receptor binding compounds and methods of use thereof
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Provided are MC4-R binding compounds of the formula XVII: wherein L2 is a linker group, and P1, P2, P3, P4, Z1, Z2, Z3, Z4, Z5, t, s, and R are a
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- AMIDINOPHENYLPYRUVIC ACID DERIVATIVES
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An amidinophenylpyruvic acid derivative of the following formula, analogs thereof and pharmaceutically acceptable salts thereof have an excellent antagonistic effect against activated blood coagulation factor VII.
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- Synthesis, anticancer activity, and inhibition of tubulin polymerization by conformationally restricted analogues of lavendustin A
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Compounds in the lavendustin A series have been shown to inhibit both protein-tyrosine kinases (PTKs) and tubulin polymerization. Since certain lavendustin A derivatives can exist in conformations that resemble both the trans-stilbene structure of the PTK
- Mu, Fanrong,Hamel, Ernest,Lee, Debbie J.,Pryor, Donald E.,Cushman, Mark
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p. 1670 - 1682
(2007/10/03)
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- Synthesis of alkenyldiarylmethane (ADAM) non-nucleoside HIV-1 reverse transcriptase inhibitors with non-Identical aromatic rings
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The existing methods for the synthesis of alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors proceed from symmetrical benzophenones and therefore result in products with identical aromatic rings. New methods have therefore been de
- Xu, Guozhang,Hartman, Tracy L.,Wargo, Heather,Turpin, Jim A.,Buckheit Jr., Robert W.,Cushman, Mark
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p. 283 - 290
(2007/10/03)
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- Preparation and photochemical rearrangements of 2-phenyl-2,5-cyclohexadien-1-ones. an efficient route to highly substituted phenols.
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[reaction: see text]. The synthesis of 2-phenyl-2,5-cyclohexadien-1-ones 1a-c and 2a-b from methyl 3-phenylbenzoate 4 and methyl 2-methoxy-5-phenylbenzoate 8 by the Birch reduction alkylation methodology is described. 1a-c and 2a-b undergo regiospecific photorearrangements at 300 nm to give tetrasubstituted phenols 14a-c and pentasubstituted phenols 18a-b, respectively. The type A photoproducts 17a-b resulting from irradiation of 2a-b at 366 nm have been isolated as approximately 1:1 diastereomer mixtures. When an optimized condition is applied, a single diastereomer of 17a is obtained.
- Guo,Schultz,Antoulinakis
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p. 1177 - 1180
(2007/10/03)
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