- 2,6-DIMETHYLPHENYLNITRENE IN LOW-TEMPERATURE MATRICES
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Photolysis of 2,6-dimethylphenyl azide on N2 matrices at 12K gives 2,6-dimethylphenylnitrene; in presence of CO, the nitrene forms the corresponding isocyanate, while on shorter wavelength irradiation, it undergoes an inefficient rearrangement to an azacycloheptatetraene.
- Dunkin, Ian R.,Donnelly, Thomas,Lockhart, Thomas S.
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Read Online
- Discovery of novel anti-angiogenesis agents. Part 8: Diaryl thiourea bearing 1H-indazole-3-amine as multi-target RTKs inhibitors
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VEGFR-2, TIE-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we designed and prepared three classes of multi-target inhibitors based on the extensive sequence homology along the kinase domain of angiogenic RTKs. Biological evaluation indicated that these multi-target inhibitors exhibited considerable potential as novel anti-angiogeneic and anticancer agents. Among them, a diaryl thiourea bearing 1H-indazole-3-amine (16a) displayed the most potent RTK inhibition and excellent selectivity. It also showed inhibition on viability of human umbilical vein endothelial cells and anti-proliferation against a broad spectrum of cancer cells. Therefore, 1H-indazole-3-amine could serve as a promising hinge binding group for multi-target inhibitors of VEGFR-2, Tie-2, and EphB4.
- Sun, Ying,Shan, Yuanyuan,Li, Chuansheng,Si, Ru,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
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p. 373 - 385
(2017/10/16)
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- Discovery of novel anti-angiogenesis agents. Part 7: Multitarget inhibitors of VEGFR-2, TIE-2 and EphB4
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Herein, we embarked on a structural optimization campaign aiming at the discovery of second generation anti-angiogenesis agents with our previously reported BPS-7 as lead compound. A library of 27 compounds has been afforded based on the highly conserved ATP-binding pocket of VEGFR-2, Tie-2, and EphB4. Several title compounds exhibited simultaneous inhibitory effects against three angiogenic RTKs. These compounds with a ‘triplet’ inhibition profile have been identified as novel anti-angiogenic and anticancer agents. The representative VDAU11 displayed prominent anti-angiogenic and anticancer potency and could be considered as a candidate for further optimization. These results indicate that N-(pyridin-2-yl)acrylamide could serve as a novel hinge-binding group of triple inhibitors.
- Li, Chuansheng,Shan, Yuanyuan,Sun, Ying,Si, Ru,Liang, Liyuan,Pan, Xiaoyan,Wang, Binghe,Zhang, Jie
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p. 506 - 518
(2017/11/14)
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- Design, synthesis and structure-activity relationships of novel diaryl urea derivatives as potential EGFR inhibitors
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Two novel series of diaryl urea derivatives 5a-i and 13a-l were synthesized and evaluated for their cytotoxicity against H-460, HT-29, A549, and MDA-MB-231 cancer cell lines in vitro. Therein, 4-aminoquinazolinyl-diaryl urea derivatives 5a-i demonstrated significant activity, and seven of them are more active than sorafenib, with IC50 values ranging from 0.089 to 5.46 μM. Especially, compound 5a exhibited the most active potency both in cellular (IC50 = 0.15, 0.089, 0.36, and 0.75 μM, respectively) and enzymatic assay (IC50 = 56 nM against EGFR), representing a promising lead for further optimization.
- Jiang, Nan,Bu, Yanxin,Wang, Yu,Nie, Minhua,Zhang, Dajun,Zhai, Xin
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- Discovery of novel VEGFR-2 inhibitors. Part 5: Exploration of diverse hinge-binding fragments via core-refining approach
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Pathological angiogenesis plays a critical role in numerous diseases including malignancy. VEGFR-2 is the central regulators in angiogenesis and has become a promising target for anticancer drug design. We have identified a novel biphenyl-aryl urea incorporated with salicyladoxime (BPS-7) as potent VEGFR-2 inhibitor. As a continuation to our previous research, various aromatic-heterocyclic were introduced as hinge-binding fragment via a core-refining approach. Interestingly, many compounds exhibited comparable VEGFR-2 inhibition to Sorafenib. In particular, 12e and 12o displayed excellent VEGFR-2 inhibitory activity with IC50 values of 0.50 nM and 0.79 nM, respectively. Several title compounds showed considerable antiproliferative activity against A549 and SMMC-7721 cells. In addition, molecular docking was performed to rationalize the efficiency of the better compounds. These results will be instructive for further inhibitor design and optimization.
- Shan, Yuanyuan,Gao, Hongping,Shao, Xiaowei,Wang, Jinfeng,Pan, Xiaoyan,Zhang, Jie
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- Palladium(0)-catalyzed carbon-Hydrogen bond functionalization for the synthesis of indoloquinazolinones
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The indoloquinazolinone ring system has attracted considerable attention as a pharmacophore, because it shows various biological activities. The reported synthetic methods for the compound are simple and direct, but are not effective for the direct synthesis of indoloquinazolinone with a methylene group at the C-6 position. A palladium(0)-catalyzed cyclization of chloroquinazolinone via C-H functionalization was developed for a concise synthesis of indoloquinazolinone derivatives. The presence of a substituent at the C-6 position is important for obtaining the product in good yield. The conformation of the reaction intermediate, in particular the N-C-Pd bond angle, is important for the regioselectivity of the reaction.
- Tsukano, Chihiro,Okuno, Masataka,Nishiguchi, Hiromi,Takemoto, Yoshiji
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supporting information
p. 1533 - 1538
(2014/06/09)
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- Synthesis of aryl urea derivatives from aryl amines and aryl isocyanates
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The present study describes the synthesis of novel diaryl urea derivatives derived from aryl amine and aryl isocyanates. The synthesized compounds are analogs of sorafenib [4-[4-[[[4-chloro-3-(trifluoromethyl)phenyl]amino]carbonyl] amino]phenoxy]-N-methylpyridine-2- carboxamide] having potential antiproliferative activity.
- Usharani,Bhujanga Rao,Reddy,Dubey
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experimental part
p. 1802 - 1806
(2011/12/22)
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- Synthesis and properties of axially-chiral N-(2,6-disubstituted)phenyl triazolones
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Certain ortho-substituted phenyl triazolone compounds are fungicidal. When two ortho-substituents are present, stable atropisomers can be isolated. Several methods for resolving racemic intermediates into the enantiomers are described, including separations of diasteromeric ester derivatives and diasteromeric salts. The intermediates were converted into products in which the absolute configuration can be correlated to biological activity.
- Brown, Richard J.,Annis, Gary,Casalnuovo, Albert,Chan, Dominic,Shapiro, Rafael,Marshall, William J.
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p. 4361 - 4375
(2007/10/03)
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- Specific nonpeptide inhibitors of puromycin-sensitive aminopeptidase with a 2,4(1H,3H)-quinazolinedione skeleton.
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Potent, specific, chemically stable and non-peptide/small-molecular inhibitors of puromycin-sensitive aminopeptidase, such as 3-(2,6-diethylphenyl)-2,4(1H,3H)-quinazolinedione (PAQ-22, 5), were prepared by the structural development of a potent PSA inhibitor, 2-(2,6-diethylphenyl)-1,2,3,4-tetrahydroisoquinoline-1,3-dione (PIQ-22, 4). The design was carried out partly by applying electrostatic potential field information obtained from PIQ-22 (4) and its derivatives based on thalidomide (2). This information revealed that a positive electrostatic potential field around the benzylic methylene in the tetrahydroisoquinoline ring is necessary for potent activity. Lineweaver-Burk plot analysis showed that PAQ-22 (5) and its derivatives inhibit puromycin-sensitive aminopeptidase (PSA) in a non-competitive manner. These potent and specific PSA inhibitors showed dose-dependent cell invasion-inhibitory activity in a Matrigel assay using mouse melanoma B16F10/L5 cells, in spite of their low cell toxicity.
- Kakuta, Hiroki,Tanatani, Aya,Nagasawa, Kazuo,Hashimoto, Yuichi
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p. 1273 - 1282
(2007/10/03)
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- Photochemical and chemical oxidation of mexiletine and tocainide. Structure elucidation of the major products
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Mexiletine (mex) and tocainide (toc) are antiarrhythmic drugs of closely related structure. Several degradation products are formed by interaction with both light and oxidizing agents in the case of mex, and only by oxidants with toc. On the basis of the
- Takacs, Mihaly,Vamos, Jozsef,Toth, Gabor,Miko-Hideg, Zsuzsa
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- Preparation of isocyanates from primary amines and carbon dioxide using Mitsunobu chemistry
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Primary alkylamines 1 and hindered arylamines 1 give high yields of isocyanates 5 when reacted with carbon dioxide and the Mitsunobu zwitterions 4 generated from dialkyl azodicarboxylates and Bu3P in dichloromethane at - 78°C. Use of Ph3P still gave high yields of isocyanates from reactions of primary alkylamines, but only low yields were obtained from reactions of aromatic amines. Reactions which failed to give high yields of isocyanates gave either carbamoylhydrazines 6 and/or dicarbamoylhydrazines 10 and/or triazolinones 7. The triazolinones were shown to arise from reactions of reactive aryl isocyanates with the Mitsunobu zwitterion. The carbamoylhydrazines were shown not to arise from reaction of isocyanate with reduced dialkyl azodicarboxylates, and a mechanism for their formation is proposed. Single-crystal X-ray analyses confirmed the structures of 6, 7, and 10.
- Saylik, Dilek,Horvath, Michael J.,Elmes, Patricia S.,Jackson, W. Roy,Lovel, Craig G.,Moody, Keith
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p. 3940 - 3946
(2007/10/03)
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- A Mitsunobu-based procedure for the preparation of alkyl and hindered aryl isocyanates from primary amines and carbon dioxide under mild conditions
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A Mitsunobu-based procedure for the preparation of alkyl and hindered aryl isocyanates in excellent yields from primary amines and carbon dioxide under very mild conditions is described.
- Horvath,Saylik,Elmes,Jackson,Lovel,Moody
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p. 363 - 366
(2007/10/03)
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- Neue Methode zur Synthese von Isocyanaten unter milden Bedingungen
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Keywords: Arendiyldiisocyanate; Di-tert-butyldicarbonat; 4-Dimethylaminopyridin; Isocyanate
- Knoelker, Hans-Joachim,Braxmeier, Tobias,Schlechtingen, Georg
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p. 2746 - 2749
(2007/10/03)
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- A Convenient and High Yielding Procedure for the Preparation of Isoselenocyanates. Synthesis and Reactivity of O-Alkylselenocarbamates.
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A high yielding one pot procedure for the preparation of isoselenocyanate from the corresponding formamide is reported.Various aromatic and aliphatic primary amines were employed in order to prepare the isoselenocyanates to establish the generality of the procedure.O-Alkylselenocarbamates of various primary, secondary and tertiary alcohols were synthesized and their stability and comparative reactivity were studied.Radical deoxygenation of the selenocarbamate of a secondary and a tertiary alcohol was accomplished under various conditions.
- Barton, Derek H. R.,Parekh, Shyamal I.,Tajbakhsh, Mahmoud,Theodorakis, Emmanouil A.,Tse, Chi-Lam
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p. 639 - 654
(2007/10/02)
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- Novel isoxazole and isoxazoline compounds with anticonvulsant activity process for their preparation and therapeutic composition containing them
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The object of the invention are anticonvulsant heterocyclic compounds of general formula: STR1 in which R1 and R2 is each selected from C1 -C4 alkyl, phenyl, benzyl, trifluoromethyl or halogen, R3 is
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- Process for the production of xylazine
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In the preparation of 2,6-dimethylphenylisothiocyanate by reacting N-(2,6-dimethylphenyl)acetamide with sodium hydride in an organic solvent to form the corresponding anion of said amide, then reacting carbon disulfide with said anion to form said 2,6-dimethylphenylisothiocyanate, unexpectedly high yields are obtained by using as the organic solvent tetrahydrofuran or a mixture of N,N-dimethylacetamide and toluene. 2,6-Dimethylphenylisothiocyanate is an intermediate in the preparation of xylazine useful, for instance, as a sedative, an analgesic and muscle relaxant.
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