- Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities
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Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90-Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a - 2d , 3a - 3g , and 4a - 4t , were designed and synthesized, and their Hsp90-Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f , with the highest tumor cell selectivity (15.4-fold), potent Hsp90-Cdc37 disruption activity (IC50= 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50= 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90-Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.
- Feng, Jia-Hao,He, Qi-Wei,Hou, Ji-Qin,Hu, Xiao-Long,Long, Huan,Wang, Bao-Lin,Wang, Hao,Wang, Quan,Wang, Rong,Ye, Wen-Cai,Zhang, Li-Xin,Zhang, Xiao-Qi
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p. 1954 - 1966
(2021/07/20)
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- Chemical synthesis, spectroscopic studies, chemical reactivity properties and bioactivity scores of an azepin-based molecule
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Azepines derived molecules are of great interest because of their multi-drug like properties and thus advantageous in biomedical field. Herein, a novel route is described for the synthesis of an azepine-based molecule, 10,11-Dibromo-10,11-dihydro- 5H-dibenzo[b,f]azepine-5-carbonyl chloride (DACC) by using dibutyltin dilaurate (DBTDL) as catalyst. The structure of DACC was elucidated by using FT-IR, NMR, and mass spectroscopic techniques. Several density functionals were considered for the study of the molecular properties of the synthesized compound. The global and local reactivity descriptors were estimated by using Conceptual Density Functional Theory (CDFT). The active sites suitable for the nucleophilic and electrophilic attacks were selected by linking them with the Fukui indices, Parr functions and condensed Dual Descriptor Δf(r). Finally, the bioactivity scores for the studied molecule were predicted through different methodologies.
- Kollur, Shiva Prasad,Castro, Joaquín Ortega,Frau, Juan,Glossman-Mitnik, Daniel
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p. 300 - 306
(2018/12/13)
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- Method for synthesizing carbamazepine
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The invention discloses a method for synthesizing carbamazepine. The method takes iminodibenzyl and chlorobenzene as raw materials and comprises the following steps: introducing triphosgene to obtainacyl chloride, performing bromination with bromine to obtain bromide, performing ammoniation with ammonium hydroxide to obtain a crude product of the carbamazepine, and finally, refining the crude product with ethanol to obtain a finished product of the carbamazepine. The acyl chlorination, bromination and ammoniation adopt chlorobenzene as a reaction solvent to reduce consumption of other solvents; in the acyl chlorination reaction, the triphosgene replaces phosgene to solve the problems of safety and environmental protection in the process; the obtained acyl chloride is not separated and isdirectly subjected to bromination dehydrogenation and ammoniation reaction to lower the operation cost; the yield of each step of the synthesis process is 93% or higher, thereby improving the production efficiency and lowering the production cost; and the synthesis process adopts self-designed novel closed equipment to reduce the consumption of chlorobenzene and ethanol, thereby being suitable forindustrial production.
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Paragraph 0008; 0009; 0010
(2018/12/13)
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- Synthetic method for carbamazepine intermediate iminostilbene carbonyl chloride
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The invention discloses a synthetic method for a carbamazepine intermediate, i.e., iminostilbene carbonyl chloride. The synthetic method is characterized by comprising the following steps: adding iminodibenzylcarbonyl chloride, chlorobenzene, an initiator and a phase-transfer catalyst, carrying out heating to 90 to 93 DEG C, adding a bromination agent for a reaction, then carrying out heating to 95 to 100 DEG C, carrying out reflux for 4 h at the same time and subjecting a reaction solution obtained after completion of reflux to post-treatment so as to obtain iminostilbene carbonyl chloride. The synthetic method has the beneficial effects that since the phase-transfer catalyst is added, escape of hydrogen bromide is reduced, the utilization rate of bromine is increased, atmospheric pollution is alleviated and production cost is lowered; and the method is suitable for industrial production.
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Paragraph 0020; 0021; 0022; 0023; 0024; 0025; 0026-0035
(2017/04/28)
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- N-heterocyclic (4-phenylpiperazin-1-yl)methanones derived from phenoxazine and phenothiazine as highly potent inhibitors of tubulin polymerization
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We report here a series of 27 10-(4-phenylpiperazin-1-yl)methanones derived from tricyclic heterocycles which were screened for effects on tumor cell growth, inhibition of tubulin polymerization, and induction of cell cycle arrest. Several analogues, among them the 10-(4-(3-methoxyphenyl)piperazine-1-carbonyl)-10H-phenoxazine-3-carbonitrile (16o), showed excellent antiproliferative properties, with low nanomolar GI50 values (16o, mean GI50 of 3.3 nM) against a large number (93) of cancer cell lines. Fifteen compounds potently inhibited tubulin polymerization. Analysis of cell cycle by flow cytometry revealed that inhibition of tumor cell growth was related to an induction of G2/M phase cell cycle blockade. Western blotting and molecular docking studies suggested that these compounds bind efficiently to β-tubulin at the colchicine binding site. Our studies demonstrate the suitability of the phenoxazine and phenothiazine core and also of the phenylpiperazine moiety for the development of novel and potent tubulin polymerization inhibitors.
- Prinz, Helge,Ridder, Ann-Kathrin,Vogel, Kirsten,B?hm, Konrad J.,Ivanov, Igor,Ghasemi, Jahan B.,Aghaee, Elham,Müller, Klaus
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p. 749 - 766
(2017/02/05)
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- Convenient syntheses of halo-dibenz[b,f]azepines and carbamazepine analogues via N-arylindoles
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The dibenz[b,f]azepine heterocyclic system and related molecules with a single 10,11-bond are important templates for well-prescribed drug molecules, notably carbamazepine (anticonvulsant), clomipramine and imipramine (antidepressants). We synthesised a range of halogenated carbamazepine analogues, in connection with metabolic and immunological studies, as probes for structure-metabolism and hypersensitive effects and have published on their metabolic behaviour. While a number of synthetic routes to such analogues are possible, we naturally sought short and efficient methods for our target compounds. In the following report we present an effective two-step synthesis of a range of dibenz[b,f]azepines from appropriate indoles via N-arylation, then acid-catalysed rearrangement, with a critical analysis of other approaches. We showed earlier that this route was effective for fluoro analogues and here present a broader review of its scope. The 5-(carboxamido) side chain of carbamazepine may be added in various ways, affording overall a convenient access to drug molecules.
- Elliott, Emma-Claire,Maggs, James L.,Park, B. Kevin,O'Neill, Paul M.,Stachulski, Andrew V.
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p. 8426 - 8434
(2013/12/04)
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- Iridium-catalyzed annulation of N -arylcarbamoyl chlorides with internal alkynes
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An iridium complex successfully catalyzed the annulation of various N-arylcarbamoyl chlorides with internal alkynes to afford 2-quinolones in good to excellent yields. The present reaction is widely applicable to substrates with various functionalities. An amide-iridacycle complex was isolated, and it is likely that such an iridacycle species is a key intermediate in the catalytic reaction.
- Iwai, Tomohiro,Fujihara, Tetsuaki,Terao, Jun,Tsuji, Yasushi
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supporting information; experimental part
p. 9602 - 9603
(2010/08/22)
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- Synthesis of 5H-dibenzo (b,f) azepine-5-{4-substitutedbenzylidene-2- methylimidazole-5-one}-carboxamides and their antioxidant activity
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A series of 5H-dibenzo (b,f) azepine-5-{4-substitutedbenzylidene-2- methylimidazole5-one}-carboxamides were synthesized and characterized on the basis of IR, 1H NMR, .and mass spectral (MS) data. The title compounds were subjected to in-vitro antioxidant testing using DPPH method. Some of the compounds showed significant antioxidant activity when compared with standard ascorbic acid.
- Kaur, Ranjit,Rao, Gopal Krishna,Pai, P. N. Sanjay
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experimental part
p. 261 - 264
(2011/12/05)
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- Synthesis of new dibenzo[b,f]azepine derivatives
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This work is focused on synthesis and chemical characterization of new polycyclic compounds having dibenzo[b,f] azepine and 10,11-dihydrodibenzo[b,f] azepine moieties. We report the synthesis of four new compounds, obtained by reacting 5H-dibenzo[b,f]azepine-5-carbonyl chloride and 10,11-dihydro-5H- dibenzo[b,f]azepine-5-carbonyl chloride with 1-phenylpiperazine, and pyrrolidine, respectively. The newly synthesized compounds were characterized using chromatographic and spectroscopic methods (HPLC-UV-VIS 1H-NMR, 13C-NMR, mass spectrometry by ESI technique).
- Balaure, Paul Catalin,Costea, Ion,Iordache, Florin,Draghici, Constantin,Enache, Cristian
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p. 935 - 942
(2011/06/21)
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- One-pot radiosynthesis of [13N]urea and [13N] carbamate using no-carrier-added [13N]NH3
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The aim of this study was to develop a practical labeling method of [ 13N]ligands using no-carrier-added [13N]NH3 with high specific activity. [13N]urea analogues [13N]1a and [13N]2a or [13N]carbamate [13N]3a were synthesized by reacting isocyanate 5a, carbamoyl chloride 6a or chloroformate 7a with [13N]NH3. The precursors 5a-7a were prepared by treating amines 8a and 9a and alcohol 10a with triphosgene in situ. These reaction mixtures were not purified and were used directly for [ 13N]ammonolysis, respectively. Using the one-pot method, we synthesized [13N]carbamazepine ([13N]4), a putative positron emission tomography ligand for brain imaging. Copyright
- Kumata, Katsushi,Takei, Makoto,Ogawa, Masanao,Kato, Koichi,Suzuki, Kazutoshi,Zhang, Ming-Rong
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experimental part
p. 166 - 172
(2010/07/02)
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- Synthesis of some novel imidazolinones
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Imidazolinone derivatives of 4a-1 have been prepared by the condensation of known heterocyclic drug derivative with 5-oxazolone derivatives, which were prepared by Erlenmeyer condensation of benzoyl glycine with different aldehydes in the presence of sodium acetate and acetic anhydride. The compounds 3a-1 were further reacted with 5H-dibenzo (b,f) azepine -5-acid hydrazide 2 to give 4a-1 in basic condition. The constitution of the products has been supported by IR, 1H-NMR, Mass spectra and elemental analysis data.
- Bhatt, Pralav V.,Wadia, Devang N.,Patel, Rajni M.,Patel, Pravin M.
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- 4'-methyl substituted fluorescein derivatives
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The present invention relates to a novel class of tracer compounds for fluorescence polarization imunoassays. The novel 4'-methyl fluorescein derivatives are conjugated to ligands via cyclic linkers.
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- Electrochemical reduction of 5H-dibenz[b, f]azepine derivatives. Part 7: Cathodic dehalogenation reactions of 10-bromo-, 10,11-dibromo- and 10,11-dibromo-10,11-dihydro-5H-dibenz[b,f]azepines. Synthesis of 10-cycloalkylamino-5H-DIBENZ[B.F]AZEPINES
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The dcp and cv investigations of 10-bromo-5 H-dibenz[b, f]azepines 1 inaprotic medium [0.11 mol/l (C2H5)4NClO4/dimethyl formamide], the interpretation of the mechanism of the cathodic debromination and the application of the debromination reactions to preparative electrolysis have been extended to vicinal dibromides as 10,11-dibromo-5 H-dibenz[b,f]azepines 3 or 4 and 10,11-dibromo-10,11-dihydro-5 H-dibenz[b,f]azepines 5 or 6. The bromo compounds 4 can be converted into the appropriate 5 H-dibenz[b, f]azepines, the bromo compounds 5 and 6 on cathodic reduction undergothe formation of the 10,11-C,C double bond. The electrochemical debromination of 3 or 4 gives the reactive intermediates 10,11-dehydro-5 Hdibenz[b,f]azepines 11, which have been trapped to 10-cycloalkylamino-5 H-dibenz[b,f]azepines 12. An alternative synthetic sequence starting from 10-bromo-5-carbamoyl-5 H-dibenz-[b,f]azepine has been used for the preparation of 12.
- Jugelt,Gessner
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p. 426 - 432
(2007/10/02)
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- Reversibility of Bromonium Ion Formation and Its Effect on Olefin Reactivity in Electrophilic Bromination. New Evidence from the 5H-Dibenzazepine System
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It has been shown that the bromonium-bromide ion-pair intermediate generated from the reaction of trans-10-bromo-10,11-dihydro-11-hydroxy-5H-dibenzazepine-5-carbonyl chloride (3) with HBr in 1,2-dichloroethane, chloroform, or carbon tetrachloride can either collapse to trans-10,11-dibromo-10,11-dihydro-5H-dibenz/b,f/azepine-5-carbonyl chloride (4) or release molecular Br2 to give 5H-dibenzazepine-5-carbonyl chloride (1).The ratio of these two products changes from ca. 7:3 in 1,2-dichloroethane to ca. 7:3 in carbon tetrachloride.Olefin 1 is similarly obtained in 50 percent yield when bromohydrin 3 is reacted with BF3.Et2O in chloroform in the presence of resorcinol, which acts as a Br+ scavenger and is transformed into its 4-bromo derivative. 5H-Dibenzazepine-5-carbonyl chloride adds Br2 in 1,2-dichloroethane at 50 deg C according to a third-order rate law with a rate constant (K3=1.9(0.1)E-2 M-2s-1) that is 4 orders of magniture lower with respect to than of the acyclic analogue cis-stilbene and gives only the trans-dibromide 4.The latter is debrominated easily to olefin 1 at 25 deg C in dimethylformamide without the addition of any specific reagent or slowly in acetonitrile in the presence of cis-stilbene as a Br2 scaverger, through the same bromonium-bromide ion-couple intermediate involved in the reaction of bromohydrin 3 with HBr.The easy reversion of this intermediate back to olefin and Br2 has been rationalized on the basis of the structural parameters obtained by X-ray diffraction of dibromide 4, showing a highly strained C(10)-C(11)-C(11a) internal angle of 121 deg and strongly unequivalent bromine atoms, with a rather longer Br-C(11) bond.
- Bellucci, Giuseppe,Bianchini, Roberto,Chiappe, Cinzia,Marioni, Franco,Spagna, Riccardo
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p. 546 - 551
(2007/10/02)
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- The Metabolism of Carbamazepine in Humans: Steric Course of the Enzymatic Hydrolysis of the 10,11-Epoxide
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Carbamazepine 10,11-oxide (1a,10b-dihydro-6H-dibenzooxirenoazepine-6-carboxamide), a key intermediate in carbamazepine metabolism, was found to be unusually resistant to enzymatic hydrolysis when incubated with microsomal and cytosolic fractions from rabbit, rat, and guinea pig livers.However, its hydrolysis product, trans-10,11-dihydro-10,11-dihydroxy-5H-dibenzoazepine-5-carboxamide, was excreted, as previously reported, both in the free and in conjugated forms, as the main metabolite in the urine of humans under carbamazepine treatment.The free diol and that obtained after treatment with β-glucuronidase/arylsulfatase were both found by Mosher's method to be formed in an enantiomeric excess of 80percent, the prevalent enantiomer having the (-)-10S,11S absolute configuration, as determined by applying the CD exciton coupling method to its bis ester.This finding confirms the pronounced enantioselectivity of the microsomal epoxide hydrolase toward meso and racemic substrates, but is in contrast with the prevalent formation of (R,R)-diols in most other known cases of enzymatic hydrolysis of epoxides.Preparatively useful syntheses of the racemic trans-10,11-dihydro-10,11-diol and of 9-(hydroxymethyl)-10-carbamoylacridan, another carbamazepine metabolite, are reported for the first time.
- Belluci, Giuseppe,Berti, Giancarlo,Chiappe, Cinzia,Lippi, Annalisa,Marioni, Franco
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p. 768 - 773
(2007/10/02)
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- A New Synthesis of 5H-Dibenzazepin-5-carboxamide (Carbamazepine)
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5H-Dibenzazepin-5-carboxamide (VI) has been synthesised starting from 2,2'-diformyldiphenylamine (III).III on cyclization with hydrazine hydrate in acetic acid gives the azepine (IV) which on treatment with COCl2 followed by ammonia affords VI, identical with an authentic sample.
- Sinha, A. K.,Agarwal, P. K.,Nizamuddin, S.
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p. 237 - 238
(2007/10/02)
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- Tegretol antigens and antibodies
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Derivatives of dibenz[b,f]azepine drugs are provided for preparation of antigens and antibodies, the antibodies finding use in immunoassays for the dibenz[b,f]azepine drugs. Specifically, N-oxoaliphatic substituted carbamoyl dibenz[b,f]azepine compounds are provided which are conjugated with antigenic materials and injected into animals for production of antibodies specific for the azepine drug.
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