- A facile hybrid 'flow and batch' access to substituted 3,4-dihydro-2: H -benzo [b] [1,4]oxazinones
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We describe a simple flow chemistry approach to libraries of ethyl 3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylates (12a-l) and N-ethyl-3-oxo-2-(substituted-phenylamino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamides (13a-l) in 38-87% yields. This scaffold is poorly described in the chemical literature. Screening against a panel of 11 cancer and one normal cell line showed that the amide linked library 13a-l was devoid of toxicity. Whereas the ester linked analogues 12b, 12c, 12g, 12j and 12l were highly cytotoxic with growth inhibition (GI50) values from 0.34 to >50 μM across all cell lines, with the 2-OH-Ph substituted 12l analogue presenting with sub-micromolar potency against the A2780 (ovarian; 0.34 ± 0.04 μM), BEC-2 (glioblastoma; 0.35 ± 0.06 μM), MIA (pancreas; 0.91 ± 0.054 μM) and SMA (murine glioblastoma; 0.77 ± 0.029 μM) carcinoma cell lines. Interestingly, the U87 glioblastoma cell line showed inherent resistance to growth inhibition by all analogues (GI50 32 to >50 μM) while the A2780 cells were highly sensitive (GI50 3.8-0.34 μM), suggesting that the analogues developed herein may be valuable lead compounds for the development of ovarian carcinoma specific cytotoxic agents. The differences in amide versus ester cytotoxicity was consitent with esterase cleaveage to release the cytotoxic warhead.
- Lin, Andrew J. S.,Russell, Cecilia C.,Baker, Jennifer R.,Frailey, Shelby L.,Sakoff, Jennette A.,McCluskey, Adam
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p. 8732 - 8742
(2016/10/03)
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- Investigation of supramolecular architectures of bent-shaped pyridine derivatives: From a three-ring crystalline compound towards five-ring mesogens
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In search of novel photoactive liquid crystals, we have synthesized a series of five-ring pyridine-based bent-core compounds bearing different substituents at the peripheral phenyl rings (CH3O, Cl and NO2). Their mesomorphic behaviour has been investigated by polarizing optical microscopy, differential scanning calorimetry and X-ray scattering, and then compared with the unsubstituted parent compound. The introduction of the methoxy groups at the peripheral phenyl rings of the bent core results in a non-mesomorphic compound, whereas the chloro- and nitro-substituted compounds form enantiotropic B1-like phases. Significant changes in the textures and transition temperatures of the mesophase have been observed under UV light. The present investigation of the mesomorphic properties of the synthesized compounds, coupled with the analysis of the molecular packing of the related three-ring compounds, will help design self-organized molecules suitable for UV indicators.
- Tri?ovi?, Nemanja,Antanasijevi?, Jelena,Rogan, Jelena,Poleti, Dejan,Tóth-Katona, Tibor,Salamonczyk, Miroslaw,Jákli, Antal,Fodor-Csorba, Katalin
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p. 6977 - 6985
(2016/08/10)
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- Design, synthesis and biological evaluation of novel EGFR/HER2 dual inhibitors bearing a oxazolo[4,5-g]quinazolin-2(1H)-one scaffold
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For the purpose of developing novel EGFR/HER2 tyrosine kinases inhibitors with high inhibition activity and low toxicity, two novel series of oxazolo[4,5-g]quinazolin-2(1H)-one derivatives as EGFR/HER2 dual inhibitors introducing two electrophiles 2-(2-bromoacetyl)ethyl and 2-(2-chloroacetoxy)ethyl group as side-chain at 1-position respectively and evaluated their EGFR and HER2 inhibition activity and toxicity comparing with Lapatinib. All these compounds were evaluated by EGFR and HER2 kinase inhibition and two anti-proliferation assays in vitro. Most of the designed compounds exhibited moderate to high inhibition activity against EGFR and HER2. Especially, compounds 11o, 11p, 12e and 12f presented high inhibition against EGFR and HER2. Furthermore, compounds 11p and 12f also had well exhibition to excellent anti-proliferation activity against human lung adenocarcinoma cell line (A549) and human breast cancer cell line (SK-Br3), and 12f also exhibited the lowest toxicity against human embryonic lung fibroblast cell line (HELF) cell. Finally, compound 12f presented remarkably higher inhibition efficacy towards tumour growth than Lapatinib in a mouse lewis lung cancer (LLC) xenograft model.
- Yin, Siyuan,Tang, Chunming,Wang, Bin,Zhang, Ying,Zhou, Liliang,Xue, Lingjing,Zhang, Can
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- Design, synthesis and biological activities of novel oxazolo[4,5- g ]quinazolin-2(1H)-one derivatives as EGFR inhibitors
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A series of oxazolo[4,5-g]quinazolin-2(1H)-one derivatives employing Erlotinib as lead compound were synthesized and evaluated for their EGFR inhibition activity. These compounds having variation at the 1 and 8-position, included ether and esters hydrophilic side-chain and aromatic head fragment, respectively. All these compounds were evaluated by EGFR inhibition and two anti-proliferation assays in vitro. Four compounds were found more potent than Erlotinib in EGFR-TK assay. Furthermore, compounds 18, 42 and 50 also had good to excellent anti-proliferation activity against human epidermoid cancer cell line (KB) and renal cell carcinoma cell line (A498). Finally, compound 50 presented remarkably higher inhibition efficacy towards tumor growth than Erlotinib in a mouse lewis lung cancer (LLC) xenograft model. Furthermore, compound 50 displayed the most distinguished effect on extending the survival period of the tumor-bearing mice.
- Yin, Siyuan,Zhou, Liliang,Lin, Jinsheng,Xue, Lingjing,Zhang, Can
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p. 462 - 475
(2016/01/09)
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- Development of hypoxia-inducible factor (HIF)-1α inhibitors: Effect of ortho-carborane substituents on HIF transcriptional activity under hypoxia
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A series of substituted ortho-carboranylphenoxyacetanilides were synthesized and evaluated for their ability to inhibit hypoxia-induced HIF-1 transcriptional activity using a cell-based reporter assay in HeLa cells expressing the HRE-dependent firefly luciferase reporter construct (HRE-Luc) and constitutively expressing CMV-driven Renilla luciferase reporter, and their ability to inhibit cell growth (GI50) using the MTT assay. Among the compounds synthesized, 1g and 1l showed significant inhibition of hypoxia-induced HIF-1 transcriptional activity (IC50: 1.9 ± 0.4 and 1.4 ± 0.2 μM, respectively). Both compounds suppressed HIF-1α accumulation in a concentration-dependent manner. The porcine heart malate dehydrogenase (MDH) refolding assay revealed that compound 1l inhibited human Hsp60 chaperone activity (IC50: 6.80 ± 0.25 μM) and this inhibition activity was higher than that of ETB (IC50: 10.9 ± 0.63 μM).
- Nakamura, Hiroyuki,Yasui, Yuka,Maruyama, Minako,Minegishi, Hidemitsu,Ban, Hyun Seung,Sato, Shinichi
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p. 806 - 810
(2013/02/25)
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- Improved iterative synthesis of linearly disassembling dendrons
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Figure presented. We report a significant improvement in the synthesis of disassembling dendritic structures by using 4-hydroxy-3-nitrobenzoic acid as the building block. We have prepared multigram quantities of first- through third-generation linearly disassembling dendrons containing a [3-N,4-O]-benzylaryl ether disassembly pathway, capped by a vanillin-derived phenyl allyl ether trigger, and a p-nitrophenoxy (PNP) reporter group. The disassembly process of these materials was initiated by allyl deprotection and monitored by the absorbance of the PNP reporter unit in the UV-vis. Modification of the disassembly conditions for the allyl trigger resulted in decreased disassembly times, decreased incubation time for onset of disassembly from minutes to seconds, and allowed observation of indicative rate differences between generations not seen with the previously reported conditions.
- Ortiz, Adrian,Shanahan, Charles S.,Sisk, David T.,Perera, Sujeewa C.,Rao, Pallavi,McGrath, Dominic V.
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experimental part
p. 6154 - 6162
(2010/11/04)
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- NOVEL CC-1065 ANALOGS AND THEIR CONJUGATES
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This invention relates to novel analogs of the DNA-alkylating agent CC-1065 and to their conjugates. Furthermore this invention concerns intermediates for the preparation of said agents and conjugates. The conjugates are designed to release their (multiple) payload after one or more activation steps and/or at a rate and time span controlled by the conjugate in order to selectively deliver and/or controllably release one or more of said DNA alkylating agents. The agents, conjugates, and intermediates can be used to treat an illness that is characterized by undesired (cell) proliferation. As an example, the agents and the conjugates of this invention may be used to treat a tumor.
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Page/Page column 155
(2010/06/17)
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- Palladium-catalyzed C-O bond formation: direct synthesis of phenols and aryl/alkyl ethers from activated aryl halides
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A simple and efficient palladium-catalyzed carbon-oxygen bond formation is reported. The palladium-tri-tert-butylphosphine complex was found to be effective in converting haloarenes to corresponding substituted phenols. This methodology offers a direct transformation of aryl halides to phenols, as well as the straightforward application to generate a wide variety of diaryl or alkyl/aryl ethers.
- Chen, Guoshu,Chan, Albert S.C.,Kwong, Fuk Yee
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p. 473 - 476
(2008/02/03)
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- Synthesis, metal complexation and biological evaluation of a novel semi-rigid bifunctional chelating agent for 99mTc labelling
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A novel bifunctional chelating agent bearing an aromatic ring has been synthesised and characterised. This ligand formed well-defined oxorhenium complexes. The analogous 99mTcO-complex was obtained in an excellent yield with high radiochemical purity (>95%). The biodistribution of the 99mTc-complex after intravenous injection studied in normal rats showed that the activity was excreted mainly via renal-urinary pathway indicating its use for labelling peptides with 99mTc.
- Gal, Julien Le,Michaud, Sandra,Gressier, Marie,Coulais, Yvon,Benoist, Eric
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p. 2904 - 2909
(2007/10/03)
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- Columnar mesophase in a novel series of banana-shaped compounds consisting of functional nitro groups
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A novel series of banana-shaped compounds with the following molecular structure has been synthesized and characterized. All the compounds synthesized in this series are found to be liquid crystalline forming a B1 phase, which has recently been designated as a columnar phase. The liquid crystalline behaviour of these compounds has been investigated by using the polarizing optical microscopy, differential scanning calorimetry and x-ray studies. The lower homologues of this series are monotropic whereas the higher ones are enantiotropic. We found that introduction of the nitro functional groups affects the mesomorphic properties in comparison to their respective unsubstituted compounds. The lower homologues of the unsubstituted ones exhibit a B1 phase whereas the higher ones a B2 phase.
- Prasad, Veena,Rao, D. S. Shankar,Prasad, S. Krishna
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- The mesophase structure of chiral liquid crystalline polysiloxanes for electro-optical applications
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Homopolysiloxanes poly(1) and poly(2) and copolysiloxanes poly(1-co-3) were synthesized. Their mesophase structures were investigated by X-ray diffraction, and the electron density profiles along the layer normal were derived. A linear response with the applied electric field was detected in the chiral smectic (C* or A*) phases of poly(1) and poly(2).
- Galli,Cesarino,Gallot,Komitov,Chiellini
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p. 147 - 160
(2007/10/03)
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- Insecticidal N-(substituted arylmethyl)-4-[bis(substituted phenyl or pyridyl)methyl]piperidines
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Compounds of the following structure, the corresponding N-oxides and agriculturally acceptable salts thereof, are disclosed as effective insecticides: whereinU is —(CH2)n—;Q is hydroxy; andR is: and whereinV, W, Y, and Z are each hydrogen;X is a five- or six-membered heterocycle; optionally substituted with bromine, chlorine, fluorine, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, haloalkoxyalkyl, or aminocarbonyl; and the heterocycle is optionally connected to the phenyl ring through a —O—, —S—, —(CH2)p, —C(O)—, or —O—(CR3R4)q linkage;R1 and R2 are independently selected from phenyl or pyridyl substituted with pentahalothio, haloalkylthio, haloalkylsulfinyl, or haloalkylsulfonyl; phenyl substituted with —OC(M)2O—, where M is bromine, chorine or fluorine, to provide a dihalobenzodioxolyl fused ring; or pyridyl substituted with —OC(M)2O— to provide a dihalodioxolenopyridyl fused ring;R3 and R4 are independently selected from hydrogen and methyl;n and p are independently 1, 2, or 3; andq is 1 or 2; with the proviso that at least one of R1 and R2 is substituted in the para position of the phenyl ring or the 5-position of the 2-pyridyl ring; each alkyl portion of said optional substituent on X wherein the optional substituent is alkyl, haloalkyl, alkoxyl, haloalkoxyl, alkoxyalkyl, or haloalkoxyalkyl contains from 1 to 4 carbon atoms; each heterocycle contains from 1 to 4 nitrogen atoms, 1 or 2 oxygen or sulfur atoms, or 1 or 2 nitrogen atoms and an oxygen or sulfur atom; and the corresponding N-oxides and agriculturally acceptable salts.
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- Optical element and compounds used in its manufacture
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An optical frequency conversion element has a wave-guiding layer which consists of a χ(2) -active ferroelectric liquid crystal. The monomeric or polymeric liquid crystal material has a periodic structure which permits the so-called quasi phase matching of a guided laser beam. The period length of the structure is equal to twice the coherence length lc =?/Δβ of the material, whereby Δβ=βo (2ω)-2βo (ω), with ω=angular frequency of the fundamental wave, 0=zero-order mode and β=propagation constant of the mode.
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- N-acylpiperazine derivative, antibacterial drug and anti-ulcer drug
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An N-acylpiperazine derivative or a salt thereof in accordance with the present invention is represented by the following formula 1: STR1 wherein R1 represents a lower alkyl, hydroxy lower alkyl, lower acyl, or arylcarbonyloxy lower alkyl group; R2 represents hydrogen atom or a lower alkyl, lower alkoxy, lower alkenyl, amino, or nitro group; R3 and R4, which are identical to or different from each other, represent hydrogen atoms, halogen atoms, or cyano, nitro, lower alkyl, or lower alkoxy groups; and n represents 0 or 1. The N-acylpiperazine derivative has anti-ulcer effect or an antibacterial activity against Helicobacter pyroli to be available for prevention or cure of ulsers.
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- Insecticidal N-(substituted arylmethyl)-4-[bis(substituted phenyl)methyl]piperidines
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Compounds of the following structure, the corresponding N-oxides and agriculturally acceptable salts, are disclosed as effective insecticides: STR1 in which U is selected from --(CH2)n -- and ethylidene; Q is selected from hydrogen, hydroxy, sulfhydryl, and fluorine; R is STR2 in which V is selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfinyl, alkylsilyloxy, dialkylamino, cyano, nitro, hydroxy, and phenyl; Y and Z are independently selected from hydrogen and alkoxy; W and X taken together is --OCH2 CH2 O--, --CH2 C(CH3)2 O--, --OC(CH3)2 O--, or --N=C(C2 H5)O--; R1 and R2 are independently selected from phenyl substituted with halogen, alkyl, haloalkyl, haloalkoxy, alkoxyalkyl, hydroxy, arylthio, alkoxy, dialkylamino, dialkylaminosulfonyl, hydroxyalkylaminocarbonyl, alkylsulfonyloxy, and haloalkylsulfonyloxy; and n is 1, 2, or 3.
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- Insecticidal n-(substituted arylmethyl)-4-[bis(substituted phenyl) methyl]pi
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Compounds of the following structure, the corresponding N-oxides and agriculturally acceptable salts, are disclosed as effective insecticides: STR1 in which U is selected from STR2 Q is selected from hydrogen, hydroxy, sulfhydryl, and fluorine; R is selected from a heterocycle having 5 or 6 ring atoms, optionally fused to a benzene ring, and STR3 wherein V, W, X, Y, Z are as defined in the specification.
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