- Pyrolytic behavior of substituted N-aminoheteroaromatics: Synthesis of pyrazolo[1,5-a]pyridine and 3-substituted 3-oxo-propionitrile derivatives
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(Chemical Equation Presented) Flash vacuum pyrolysis (FVP) of 1,7-bis-(3-aroylideneamino)-4,6,10,12-tetramethyl-2,8-dioxo-1, 7-diazacyclododeca-3,5,9,11-tetraene-3,9-dicarbonitriles 11a-c at 650°C and 0.02 Torr yielded 5,7-dimethyl-3-(4-methylbenzoyl)-pyrazolo[1,5-a]pyridine-4- carbonitrile 14, 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 16 and 3-aryl-3-oxo-propionitriles 17a,b. A plausible mechanism is suggested to account for the formation of the products.
- Al-Awadi, Nouria A.,Abdelkhalik, Mervat,Patel, Mehul,Dib, Hicham H.
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Read Online
- Synthesis and in vitro antiproliferative activity of certain novel pyrazolo[3,4-b]pyridines with potential p38α MAPK-inhibitory activity
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Novel series of pyrazolo[3,4-b]pyridines 9a–j and 14a–f were prepared via a one-pot three-component reaction. Compounds 9a–j were synthesized by the reaction of 3-(4-chlorophenyl)?1-phenyl-1H-pyrazol-5-amine (4) with benzoyl acetonitriles 3a,b and aldehydes 5a–e, whereas the spiro derivatives 14a–f were synthesized by the reaction of pyrazole derivative 4 with 3a–c and indoline-2,3-diones 10a,b. Screening of the antiproliferative activity of 9a–j and 14a–f revealed that 14a and 14d were the most potent analogues against HepG2 and HeLa cells, with IC50 = 4.2 and 5.9 μM, respectively. Moreover, compounds 9c and 14a could promote cell cycle disturbance and apoptosis in HepG2 cells, as evidenced by DNA flow cytometry and Annexin V-FITC/PI assays. Cell cycle analysis of 9c and 14a indicated a reduction in HepG2 cells in the G1 phase, with arrest in the S phase and the G2/M phase, respectively. Also, 9c and 14a are good apoptotic inducers in the HepG2 cell line. Furthermore, compounds 9h and 14d stood out as the most efficient antiproliferative agents in the NCI 60-cell line panel screening, with mean GI % equal to 60.3% and 55.4%, respectively. Additionally, 9c, 9h, 14a, and 14d showed good inhibitory action against the cellular pathway regulator p38α kinase, with IC50 = 0.42, 0.41, 0.13, and 0.64 μM, respectively. A docking study was carried out on the p38α kinase active site, showing a binding mode comparable to that of reported p38 mitogen-activated protein kinase inhibitors. These newly discovered pyrazolo[3,4-b]pyridines could be considered as potential candidates for the development of newly targeted anticancer agents.
- Abdel-Aziz, Hatem A.,Farahat, Aya A.,Samir, Eman M.,Serya, Rabah A. T.,Zaki, Mayssoune Y.
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- One-pot three-component synthesis of novel pyrazolo[3,4-b]pyridines as potent antileukemic agents
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In the current study, we report on the development of novel series of pyrazolo[3,4-b]pyridine derivatives (8a-u, 11a-n, and 14a,b) as potential anticancer agents. The prepared pyrazolo[3,4-b]pyridines have been screened for their antitumor activity in vitro at NCI-DTP. Thereafter, compound 8a was qualified by NCI for full panel five-dose assay to assess its GI50, TGI and LC50 values. Compound 8a showed broad-spectrum anti-proliferative activities over the whole NCI panel, with outstanding growth inhibition full panel GI50 (MG-MID) value equals 2.16 μM and subpanel GI50 (MG-MID) range: 1.92–2.86 μM. Furthermore, pyrazolo[3,4-b]pyridines 8a, 8e-h, 8o, 8u, 11a, 11e, 11h, 11l and 14a-b were assayed for their antiproliferative effect against a panel of leukemia cell lines (K562, MV4-11, CEM, RS4;11, ML-2 and KOPN-8) where they possessed moderate to excellent anti-leukemic activity. Moreover, pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b were further explored for their effect on cell cycle on RS4;11 cells, in which they dose-dependently increased populations of cells in G2/M phases. Finally we analyzed the changes of selected proteins (HOXA9, MEIS1, PARP, BcL-2 and McL-1) related to cell death and viability in RS4;11 cells via Western blotting. Collectively, the obtained results suggested pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b as promising lead molecules for further optimization to develop more potent and efficient anticancer candidates.
- Abdel-Aziz, Hatem A.,Barghash, Reham F.,Eldehna, Wagdy M.,Kovalová, Markéta,Kry?tof, Vladimír,Vojá?ková, Veronika
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- Modular synthesis and antiproliferative activity of new dihydro-1H-pyrazolo[1,3-b]pyridine embelin derivatives
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A set of new dihydro-1H-pyrazolo[1,3-b]pyridine and pyrazolo[1,3-b]pyridine embelin derivatives was synthesized through a multicomponent reaction from natural embelin, 3-substituted-5-aminopyrazoles and aldehydes. The synthesized compounds were evaluated against three hematologic tumor cell lines, HEL (acute erythroid leukemia), K-562 (chronic myeloid leukemia) and HL-60 (acute myeloid leukemia), and five breast cancer cell lines (SKBR3, MCF-7, MDA-MB-231, BT-549, HS-578T). The primate non-malignant kidney Vero cell line was used as the control of cytotoxicity. From the obtained results, some structure–activity relationships were out-lined. Furthermore, in silico prediction of physicochemical properties and ADME parameters were determined for the derivatives with the best antiproliferative values.
- Amesty, ángel,Estévez-Braun, Ana,Fernández-Pérez, Leandro,Guerra, Borja,Guerra-Rodríguez, Miguel,Martín-Acosta, Pedro
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- Deadly KCN and pricey metal free track for accessing β-ketonitriles employing mild reaction conditions
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A one pot synthesis of β-ketonitriles from readily accessible 3-chloropropenals using economically benign iodine, aqueous ammonia and sodium hydroxide solution, employing mild reaction conditions have been described. This report presents a convenient, inexpensive, highly toxic-matter-free and eco-friendly approach for β-ketonitriles.
- Sharma, Pawan K.,Kumar, Rajiv,Ram, Sita,Chandak, Navneet
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supporting information
p. 1847 - 1856
(2021/04/26)
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- Selective Synthesis of β-Ketonitriles via Catalytic Carbopalladation of Dinitriles
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A practical, convenient, and highly selective method of synthesizing β-ketonitriles from the Pd-catalyzed addition of organoboron reagents to dinitriles has been developed. This method provides excellent functional-group tolerance, a broad scope of substrates, and the convenience of using commercially available substrates. The method is expected to show further utility in future synthetic procedures.
- Zeng, Ge,Liu, Jichao,Shao, Yinlin,Zhang, Fangjun,Chen, Zhongyan,Lv, Ningning,Chen, Jiuxi,Li, Renhao
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p. 861 - 867
(2021/01/09)
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- Synthesis and Structure-Activity Relationship of Dual-Stage Antimalarial Pyrazolo[3,4- b]pyridines
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Malaria remains one of the most deadly infectious diseases, causing hundreds of thousands of deaths each year, primarily in young children and pregnant mothers. Here, we report the discovery and derivatization of a series of pyrazolo[3,4-b]pyridines targeting Plasmodium falciparum, the deadliest species of the malaria parasite. Hit compounds in this series display sub-micromolar in vitro activity against the intraerythrocytic stage of the parasite as well as little to no toxicity against the human fibroblast BJ and liver HepG2 cell lines. In addition, our hit compounds show good activity against the liver stage of the parasite but little activity against the gametocyte stage. Parasitological profiles, including rate of killing, docking, and molecular dynamics studies, suggest that our compounds may target the Qo binding site of cytochrome bc1.
- Eagon, Scott,Hammill, Jared T.,Sigal, Martina,Ahn, Kevin J.,Tryhorn, Julia E.,Koch, Grant,Belanger, Briana,Chaplan, Cory A.,Loop, Lauren,Kashtanova, Anna S.,Yniguez, Kenya,Lazaro, Horacio,Wilkinson, Steven P.,Rice, Amy L.,Falade, Mofolusho O.,Takahashi, Rei,Kim, Katie,Cheung, Ashley,Dibernardo, Celine,Kimball, Joshua J.,Winzeler, Elizabeth A.,Eribez, Korina,Mittal, Nimisha,Gamo, Francisco-Javier,Crespo, Benigno,Churchyard, Alisje,García-Barbazán, Irene,Baum, Jake,Anderson, Marc O.,Laleu, Beno?t,Guy, R. Kiplin
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p. 11902 - 11919
(2020/11/26)
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- Cracking under internal pressure: Photodynamic behavior of vinyl azide crystals through N2release
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When exposed to UV light, single crystals of the vinyl azides 3- azido-1-phenylpropenone (1a), 3-azido-1-(4-methoxyphenyl)propenone (1b), and 3-azido-1-(4-chlorophenyl)propenone (1c) exhibit dramatic mechanical effects by cracking or bending with the release of N2. Mechanistic studies using laser flash photolysis, supported by quantum mechanical calculations, show that each of the vinyl azides degrades through a vinylnitrene intermediate. However, despite having very similar crystal packing motifs, the three compounds exhibit distinct photomechanical responses in bulk crystals. While the crystals of 1a delaminate and release gaseous N2 indiscriminately under paraffin oil, the crystals of 1b and 1c visibly expand, bend, and fracture, mainly along specific crystallographic faces, before releasing N2. The photochemical analysis suggests that the observed expansion is due to internal pressure exerted by the gaseous product in the crystal lattices of these materials. Lattice energy calculations, supported by nanoindentation experiments, show significant differences in the respective lattice energies. The calculations identify critical features in the crystal structures of 1b and 1c where elastic energy accumulates during gas release, which correspond to the direction of the observed cracks. This study highlights the hitherto untapped potential of photochemical gas release to elicit a photomechanical response and motility of photoreactive molecular crystals.
- Shields, Dylan J.,Karothu, Durga Prasad,Sambath, Karthik,Ranaweera, Ranaweera A. A. Upul,Schramm, Stefan,Duncan, Alexander,Duncan, Benjamin,Krause, Jeanette A.,Gudmundsdottir, Anna D.,Naumov, Pan?e
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p. 18565 - 18575
(2020/12/01)
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- One-Pot Four-Component Coupling Approach to Polyheterocycles: 6 H-Furo[3,2- f]pyrrolo[1,2- d][1,4]diazepine
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A novel polyheterocyclic chemical space, 6H-furo[3,2-f]pyrrolo[1,2-d][1,4]diazepine, was generated by a one-pot four-component coupling reaction where multiple bonds (three C-C, one C-O, and one C-N) were formed through a domino sequence. Two heterocyclic rings (furan and diazepine) were sequentially constructed from the monocyclic pyrrole derivative under environment-friendly reaction conditions to furnish the tricyclic fused scaffold.
- Yoon, Seok Hyun,Kim, Sung June,Kim, Ikyon
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p. 15082 - 15091
(2020/12/02)
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- 6H-THIENO[2,3-E][1,2,4]TRIAZOLO[3,4-C][1,2,4]TRIAZEPINE DERIVATIVE
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The 6H-thieno[2,3-e][1,2,4]triazolo[3,4-c][1,2,4]triazepine derivatives or salts thereof of the present invention have BRD4 inhibitory activity, and thus, they are useful as medicaments, in particular, as prophylaxis and/or therapeutic agents for diseases associated with BRD4.
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- Antitumor properties of certain spirooxindoles towards hepatocellular carcinoma endowed with antioxidant activity
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In the current medical era, spirooxindole motif stands out as a privileged heterospirocyclic scaffold that represents the core for a wide range of bioactive naturally isolated products (such as Strychnofoline and spirotryprostatins A and B) and synthetic compounds. Interestingly, no much attention has been paid to develop spirooxindole derivatives with dual antioxidant and anticancer activities. In this context, a series of spirooxindoles 6a-p was examined for their anticancer effect towards HepG2 hepatocellular carcinoma and PC-3 prostate cancer cell lines. Spirooxindole 6a was found to be an efficient anti-proliferative agent towards both HepG2 and PC-3 cells (IC50 = 6.9 and 11.8 μM, respectively). Afterwards, spirooxindole 6a was assessed for its apoptosis induction potential in HepG2 cells, where its pro-apoptotic impact was approved via the significant elevation in the Bax/Bcl-2 ratio and the expression levels of caspase-3,.
- Al-Rashood, Sara T.,Hamed, Ahmed R.,Hassan, Ghada S.,Alkahtani, Hamad M.,Almehizia, Abdulrahman A.,Alharbi, Amal,Al-Sanea, Mohammad M.,Eldehna, Wagdy M.
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p. 831 - 839
(2020/04/08)
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- Structure guided design of potent indole-based ATX inhibitors bearing hydrazone moiety with tumor suppression effects
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ATX was capable of catalyzing the hydrolysis of LPC to the lipid mediator LPA which attracted considerable attention on the development of potent ATX inhibitors. Herein, driven by the HTS product indole-based lead 1, a hybridization strategy was utilized to construct the trifluoroacetyl hydrazone moiety through assembling the phenyl thiazole fragment to the indole skeleton of lead 1. After a systematic structure guided optimization, by cycling the phenyl thiazole to the compacted benzothiazole or decreasing the lipophilicity, two promising ATX inhibitors (9j and 25a) were identified with IC50 values of 2.1 nM and 19.0 nM, respectively. All compounds were tested a panel of cancer cell lines and a preliminary affinity on breast cancer cell lines (SI > 16.5) were observed which shed a light on their potential application of breast cancer relevant cases. Through a dedicated docking study, the intramolecular pseudo-ring within the trifluoroacetylhydrazone moiety played a significant role in constraining the binding poses of 9j and 25a. Finally, a binding free energy calculation was conducted to examine the contribution of different interactions in binding affinity.
- Guo, Ming,Jia, Fang,Jiang, Nan,Lei, Hongrui,Li, Changtao,Yang, Yu,Zhai, Xin,Zhu, Minglin
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- Identification of diphenylalkylisoxazol-5-amine scaffold as novel activator of cardiac myosin
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To identify novel potent cardiac myosin activator, a series of diphenylalkylisoxazol-5-amine compounds 4–7 have been synthesized and evaluated for cardiac myosin ATPase activation. Among the 37 compounds, 4a (CMA at 10 μM = 81.6%), 4w (CMA at 10 μM = 71.2%) and 6b (CMA at 10 μM = 67.4%) showed potent cardiac myosin activation at a single concentration of 10 μM. These results suggested that the introduction of the amino-isoxazole ring as a bioisostere for urea group is acceptable for the cardiac myosin activation. Additional structure–activity relationship (SAR) studies were conducted. Para substitution (-Cl, –OCH3, -SO2N(CH3)2) to the phenyl rings or replacement of a phenyl ring with a heterocycle (pyridine, piperidine and tetrahydropyran) appeared to attenuate cardiac myosin activation at 10 μM. Additional hydrogen bonding acceptor next to the amino group of the isoxazoles did not enhance the activity. The potent isoxazole compounds showed selectivity for cardiac myosin activation over skeletal and smooth muscle myosin, and therefore these potent and selective isoxazole compounds could be considered as a new series of cardiac myosin ATPase activators for the treatment of systolic heart failure.
- Boggu, Pulla Reddy,Venkateswararao, Eeda,Manickam, Manoj,Sharma, Niti,Kang, Jong Seong,Jung, Sang-Hun
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- Microwave synthesis of 1-aryl-1H-pyrazole-5-amines
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A microwave-mediated synthesis of 1H-pyrazole-5-amines utilizing 1 M HCl at 150 °C was developed in order to provide products in a matter of minutes with minimal purification. Most reactions are complete in only 10 min and can be isolated via a simple filtration without the need for further purification by column chromatography or recrystallization. This method tolerates a range of functional groups and can be performed on milligram to gram scales.
- Everson, Nikalet,Yniguez, Kenya,Loop, Lauren,Lazaro, Horacio,Belanger, Briana,Koch, Grant,Bach, Jordan,Manjunath, Aashrita,Schioldager, Ryan,Law, Jarvis,Grabenauer, Megan,Eagon, Scott
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- One-pot three-component synthesis of a series of 4-aroyl-1,6-diaryl-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbonitriles in the presence of aluminum oxide as a nanocatalyst
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[Figure not available: see fulltext.] One-pot three-component reaction of arylglyoxals, 3-aryl-3-oxopropanenitriles, and 5-amino-1-aryl-3-methylpyrazoles using various solvent systems and different catalysts under reflux conditions afforded the corresponding 4-aroyl-1,6-diaryl-3-methyl-1H-pyrazolo[3,4-b]- pyridine-5-carbonitrile derivatives. The best yields (70–91%) were obtained using Al2O3 as a nanocatalyst in H2O–EtOH, 1:1, under reflux conditions. The simplicity of workup procedure, the novelty of pyrazolopyridines, green solvent system, easy preparation of a nanocatalyst, and good to excellent yields of the products are the advantages of this synthetic strategy. The structures of all products were confirmed by FT-IR, 1H and13C NMR, and mass spectral data.
- Arlan, Fatemeh Majidi,Khalafy, Jabbar,Maleki, Ramin
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- One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells
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Triple-negative breast cancer (TNBC) is a highly aggressive malignancy with limited treatment options due to its heterogeneity and the lack of well-defined molecular targets. In our endeavour towards the development of novel anti-TNBC agents, herein we report a one-pot three-component synthesis of novel spirooxindoles 6a–p, and evaluation of their potential anti-proliferative activity towards TNBC MDA-MB-231 cells. Spirooxindoles 6a, 6e and 6i emerged as the most potent analogues with IC50 = 6.70, 6.40 and 6.70 μM, respectively. Compounds 6a and 6e induced apoptosis in MDA-MB-231 cells, as evidenced by the up-regulation of the Bax and down-regulation of the Bcl-2, besides boosting caspase-3 levels. Additionally, 6e displayed significant increase in the percent of annexin V-FITC positive apoptotic cells from 1.34 to 44%. Furthermore, spirooxindoles 6e and 6i displayed good inhibitory activity against EGFR (IC50 = 120 and 150 nM, respectively). Collectively, these data demonstrated that 6e might be a potential lead compound for the development of effective anti-TNBC agents.
- Eldehna, Wagdy M.,El-Naggar, Dina H.,Hamed, Ahmed R.,Ibrahim, Hany S.,Ghabbour, Hazem A.,Abdel-Aziz, Hatem A.
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p. 309 - 318
(2018/03/01)
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- One-pot dichlorinative deamidation of primary β-ketoamides
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An approach to the dichlorinative deamidation of primary β-ketoamides through ketonic cleavage is described, and a series of α,α-dichloroketones were furnished mostly in the presence of TEMPO. Based on control experiments, a mechanism involving tandem dichlorination and deamidation is proposed to interpret the observed reactivity.
- Zheng, Congke,Zhang, Xiaohui,Ijaz Hussain, Muhammad,Huang, Mingming,Liu, Qing,Xiong, Yan,Zhu, Xiangming
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p. 574 - 577
(2017/01/16)
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- One-pot synthesis of benzoylacetonitriles through sequential Pd-catalyzed carbonylation and decarboxylation
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Benzoylacetonitrile were prepared through sequential carbonylation and decarboxylation. The palladium-catalyzed carbonylation of aryl iodides and methyl cyanoacetate using Mo(CO)6 as a carbon monoxide source afforded beta-keto cyanoesters, and then the subsequent reaction with Li/H2O produced the desired benzoylacetonitriles.
- Lee, Sunwoo,Kim, Han-Sung,Min, Hongkeun,Pyo, Ayoung
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p. 239 - 242
(2015/12/31)
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- Palladium-Catalyzed Carbonylative α-Arylation of tert -Butyl Cyanoacetate with (Hetero)aryl Bromides
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A three-component coupling protocol has been developed for the generation of 3-oxo-3-(hetero)arylpropanenitriles via a carbonylative palladium-catalyzed α-arylation of tert-butyl 2-cyanoacetates with (hetero)aryl bromides followed by an acid-mediated decarboxylation step. Through the combination of only a stoichiometric loading of carbon monoxide and mild basic reaction conditions such as MgCl2 and dicyclohexylmethylamine for the deprotonation step, an excellent functional group tolerance was ensured for the methodology. Through the use of 13C-labeled carbon monoxide generated from 13COgen, the corresponding 13C-isotopically labeled β-ketonitriles were obtained, and these products could subsequently be converted into cyanoalkynes and 3-cyanobenzofurans with site specific 13C-isotope labeling. (Chemical Equation Presented).
- Jensen, Mikkel T.,Juhl, Martin,Nielsen, Dennis U.,Jacobsen, Mikkel F.,Lindhardt, Anders T.,Skrydstrup, Troels
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p. 1358 - 1366
(2016/03/01)
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- Double HDAC/BRD4 inhibitor and its preparation method and application (by machine translation)
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The invention has disclosed a kind of double HDAC/BRD4 inhibitor and its preparation and application, double HDAC/BRD4 inhibitor structural formula such as formula 16 as shown. The invention also discloses the above-mentioned double HDAC/BRD4 inhibitor preparation method and its application in the preparation of medicament. This invention, through the Linker HDAC inhibitors with the pharmacophore BRD4 inhibitor potency of splicing group, with a double HDAC/BRD4 inhibiting effect of the novel dual-HDAC/BRD4 inhibitor. The preparation method of this invention is simple, mild condition, it is easy to realize. (by machine translation)
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Paragraph 0067; 0068; 0069; 0070; 0071; 0072
(2016/10/17)
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- A new strategy for synthesis of 9-benzoyl-4-methylpyrano[2,3-f]chromene-2,8-dione using L-proline as a novel and efficient catalyst
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We report the high yield synthesis of novel 9-benzoyl-4-methylpyrano[2,3-f]chromene-2,8-dione derivatives obtained by the reaction of 8-formyl-7-hydroxy-4-methylcoumarin with various active methylene compounds. A mechanism of the tandem Knoevenagel condensation and cyclisation reaction is proposed. Structures of all compounds were elucidated on the basis of 1H and 13C NMR, and mass spectrometry, and elemental analysis.
- Goud,Rao,Hemasri,Thirupathi
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p. 2732 - 2736
(2017/03/22)
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- Umpolung Strategy for Synthesis of β-Ketonitriles through Hypervalent Iodine-Promoted Cyanation of Silyl Enol Ethers
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An efficient method to synthesize β-ketonitriles from silyl enol ethers by an umploung hypervalent iodine(III)-CN species generated in situ from PhIO/BF3·Et2O/TMSCN has been developed for the first time. This method can be applied to structurally diverse aromatic and aliphatic substrates and further extended to preparation of bioactive compounds like 5-aminopyrazole and 5-aminoisoxazole.
- Shen, Hang,Li, Jiaqiang,Liu, Qing,Pan, Jing,Huang, Ruofeng,Xiong, Yan
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p. 7212 - 7218
(2015/07/28)
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- BROMODOMAIN-INHIBITING COMPOUNDS AND PHARMACEUTICAL COMPOSITION COMPRISING SAME FOR PREVENTING OR TREATING A CANCER
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Provided is a novel compound having bromodomain and extra terminal domain (BET) protein inhibiting activities, and a pharmaceutical composition comprising the same which can be useful for prevention or treatment of precancerous transformation or cancer.
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Paragraph 67; 68
(2015/11/27)
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- Divergent Reactivity in the Reaction of β-Oxodithioesters and Hydroxylamine: Access to β-Ketonitriles and Isoxazoles
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Starting from β-oxodithioesters and hydroxylamine, two completely different transformations afford either β-ketonitriles or isoxazoles with high chemoselectivity depending on the reaction conditions. The reaction of β-oxodithioesters with hydroxylamine in EtOH at room temperature in daylight gave β-ketonitriles in high yields. On the other hand, 3-methylthio-isoxazoles were efficiently obtained as the final products by heating the mixture of β-oxodithioesters and hydroxylamine in HOAc at 90 °C.
- Li, Jiaheng,Ma, Wei,Ming, Wenbo,Xu, Cong,Wei, Na,Wang, Mang
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p. 11138 - 11142
(2015/11/18)
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- Chemo- And stereoselective reduction of β-keto-α-oximino nitriles by using baker's yeast
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The baker's yeast mediated reduction of β-keto-α-oximino nitriles 3 at 20 ° C gave β-hydroxy-α-oximino nitriles 4 in high yields with high enantiomeric purity [enantiomeric excess (ee) values >99%]. At room temperature, the same reaction afforded the product in a slightly lower yield. The β-hydroxy-α-oximino nitriles 4 were obtained as single stereoisomers according to chiral GC-MS analyses and the 1H and 19F NMR spectra of the corresponding Mosher esters. The abso-lute stereochemistry of alcohol 4a was determined by hydrolysis of its oximino nitrile group followed by conversion into its corresponding α-hydroxy ester. The β-hydroxy-α-oximino nitrile products were further submitted to oxime- and nitrileselective transformations. This chemo- and stereoselective reduction can be used to generate important chiral building blocks.
- Mo, Kilwoong,Kang, Soon Bang,Kim, Youseung,Lee, Yong Sup,Lee, Jae Wook,Keum, Gyochang
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p. 1137 - 1143
(2015/02/19)
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- BENZENE SULFONAMIDES AS CCR9 INHIBITORS
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The present invention relates to compounds useful as CCR9 modulators, to compositions containing them, to methods of making them, and to methods of using them. In particular, the present invention relates to compounds capable of modulating the function of the CCR9 receptor by acting as partial agonists, antagonists or inverse agonists. Such compounds may be useful to treat, prevent or ameliorate a disease or condition associated with CCR9 activation, including inflammatory and immune disorder diseases or conditions such as inflammatory bowel diseases (IBD).
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- Direct synthesis of pyrazoles from esters using tert-butoxide-assisted C-(C=O) coupling
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This paper describes the direct synthesis of pyrazoles from esters that comprises two sequential reactions: tert-butoxide-assisted C-C(=O) coupling reaction to yield β-ketonitrile or α,β-alkynone intermediates, and condensation by hydrazine addition. The method reported allows for easy control of the regioselectivity and structure of substituents at N-1, C-3, C-4 and/or C-5 positions.
- Kim, Bo Ram,Sung, Gi Hyeon,Ryu, Ki Eun,Lee, Sang-Gyeong,Yoon, Hyo Jae,Shin, Dong-Soo,Yoon, Yong-Jin
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supporting information
p. 9201 - 9204
(2015/06/08)
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- Synthesis and biological evaluation of pyrazolo[3,4-b]pyridin-4-ones as a new class of topoisomerase II inhibitors
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A series of 1,3,6-triphenylpyrazolo[3,4-b]pyridin-4-one derivatives was designed, synthesized and evaluated for cytotoxic activity in A375 human melanoma and human erythroleukemia (HEL) cells. The new pyrazolopyridones displayed comparable activities to the antitumor compound etoposide. The inhibitory effect of compounds 17, 18, 27 and 32 against topoisomerase II-mediated cleavage activities was measured finding good correlation with the results obtained from MTS assay. Docking studies into bacterial topoisomerase II (DNA Gyrase), topoisomerase IIα and topoisomerase IIβ binding sites in the DNA binding interface were performed.
- Tabrizi, Mojgan Aghazadeh,Baraldi, Pier Giovanni,Baraldi, Stefania,Prencipe, Filippo,Preti, Delia,Saponaro, Giulia,Romagnoli, Romeo,Gessi, Stefania,Merighi, Stefania,Stefanelli, Angela,Fazzi, Debora,Borea, Pier Andrea,Maia, Rodolfo Couto,Romeiro, Nelilma C.,Fraga, Carlos A.M.,Barreiro, Eliezer J.
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p. 342 - 353
(2016/10/11)
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- Specific 1,2-Hydride Shift in the Boron Trifluoride Catalyzed Reactions of Aromatic Aldehydes with Diazoacetonitrile: Simple Synthesis of β-Ketonitriles
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A series of β-ketonitriles was synthesized within 30 min under mild conditions through the BF3 ·OEt2-catalyzed addition reactions of diazoacetonitrile to aromatic aldehydes and subsequent 1,2-hydride shift. This method is advantageous in that it is operationally simple, mild and metal-free conditions are used, the substrate scope is wide, and the products are obtained in moderate to high yields (up to 81 %). Additionally, γ,δ-unsaturated β-ketonitriles are also accessible by this method by using cinnamaldehydes.
- Yang, Zhanhui,Son, Kwon-Il,Li, Siqi,Zhou, Bingnan,Xu, Jiaxi
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supporting information
p. 6380 - 6384
(2016/02/18)
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- Cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from N-allyl enamines
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An efficient iodine-mediated cascade synthesis of 3-aza-bicyclo[3.1.0]hex-2-ene derivatives from easily prepared N-allyl enamines has been developed. The advantages of the reaction include facilitative preparation of substrates 3a-t, good functional group tolerance and transition-metal-free conditions.
- Zhai, Sheng-Xian,Dong, Hong-Ru,Chen, Zi-Bao,Hu, Yi-Ming,Dong, Heng-Shan
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p. 8405 - 8412
(2015/03/04)
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- Copper-catalyzed Aerobic Oxidative coupling of Aromatic Alcohols and Acetonitrile to β-Ketonitriles
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A practical, convenient, and cheap coppercatalyzed aerobic oxidative coupling of aromatic alcohols and acetonitrile to β-ketonitriles has been developed. The green C-C bond formation involving the loss of two hydrogen atoms from the corresponding two carbons, respectively, unlocks opportunities for markedly different synthetic strategies.
- Shen, Jiaxuan,Yang, Dejun,Liu, Yuxiao,Qin, Shuangshuang,Zhang, Jingwu,Sun, Jiangkai,Liu, Chunhui,Liu, Chaoyang,Zhao, Xiaomei,Chu, Changhu,Liu, Renhua
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supporting information
p. 350 - 353
(2014/04/03)
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- An efficient synthesis of 2-aminothiophenes via the gewald reaction catalyzed by an N-methylpiperazine-functionalized polyacrylonitrile fiber
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A new N-methylpiperazine-functionalized polyacrylonitrile fiber has been developed to catalyze the Gewald reaction between 2,5-dihydroxy-1,4-dithiane and activated nitriles to afford 3-substituted 2-aminothiophenes in good to excellent yields (65-91%). Low catalyst loading (8.0 mol%), simple procedure, high yields, excellent recyclability, and reusability (up to 10 times with minimal loss of catalytic activity) are attractive features of this fiber catalyst. Georg Thieme Verlag Stuttgart · New York.
- Ma, Lichao,Yuan, Liwei,Xu, Changzhu,Li, Guowei,Tao, Minli,Zhang, Wenqin
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- Synthesis of β-ketonitriles, α,β-alkynones and biscabinols from esters using tert-butoxide-assisted C(=O)-C (i.e., acyl-C) coupling under ambient conditions
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We demonstrated the synthesis of β-ketonitriles, α,β- alkynones, and biscarbinols using tert-butoxide-assisted C(CO)-C (i.e., acyl-C) coupling of esters under ambient conditions. tert-Butoxide-assisted C(CO)-C (i.e., acyl-C) coupling of esters with cyanomethylenes and acetylenes under transition metal-free ambient conditions gives β-ketonitriles, α,β-alkynones and/or aryl bis(phenylethynyl)carbinols in moderate-to-good yields. It is noteworthy that this is a rapid, facile, and efficient process under ambient conditions, and use of cheap and stable starting materials.
- Kim, Bo Ram,Lee, Hyung-Geun,Kang, Seung-Beom,Jung, Kwang-Ju,Sung, Gi Hyeon,Kim, Jeum-Jong,Lee, Sang-Gyeong,Yoon, Yong-Jin
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p. 10331 - 10336
(2013/11/19)
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- Palladium-catalyzed carbonylation with Mo(CO)for the synthesis of benzoylacetonitriles
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Benzoylacetonitriles were synthesized by the palladium-catalyzed carbonylation of aryl iodides and trimethylsilylacetonitrile using Mo(CO)as a carbon monoxide source. Pd(PPhCland CuFwere employed as the catalyst and activator, respectively. A variety of aryl iodides bearing alkyl, alkoxy, fluoro, chloro, bromo, nitrile, ester, and ketone groups afforded the corresponding benzoylacetonitriles in moderate to good yields. Georg Thieme Verlag Stuttgart ? New York.
- Pyo, Ayoung,Park, Ahbyeol,Jung, Hyunmin,Lee, Sunwoo
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supporting information
p. 2885 - 2888
(2012/10/29)
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- Synthesis of benzoylacetonitriles from Pd-catalyzed carbonylation of aryl iodides and trimethylsilylacetonitrile
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Palladium-catalyzed carbonylation of aryl iodides and trimethylsilylacetonitrile to produce benzoylacetonitrile derivatives through a one-pot, three-component reaction is described. This preparation method provides good yields of the carbonylated products without any additional ligands. It has a broad substrate scope with a high tolerance for a variety of functional groups.
- Park, Ahbyeol,Lee, Sunwoo
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supporting information; experimental part
p. 1118 - 1121
(2012/03/27)
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- Phase transfer catalyst in grindstone synthesis of 3-oxopropanenitrile: One pot synthesis of polysubstituted amino thiophenes
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The chemoselective SN2 reaction of ω-bromoacetophenone with sodium cyanide or potassium cyanide in DMF-water or in biphasic solvent toluene-water using tetrabutylammonium bromide (TBAB) as phase-transfer catalyst, performed by grinding, furnished 3-oxopropanenitriles 2 as the sole product in 70-80% yield, while in ethanolwater, mixture of compound 2 and oxirane 3 were obtained. The obtained 3-oxopropanenitriles 2 were used for one pot synthesis of 2-amino-3-carbonitrile thiophenes.
- Patil, Shivaraj P.,Kanawade, Shrikant B.,Shinde, Madhukar P.,Toche, Raghunath B.
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- Biocatalytic strategy toward asymmetric β-hydroxy nitriles and γ-amino alcohols
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A library of 20 bakers' yeast reductases, that are overexpressed in Escherichia coli, were screened against a variety of β-keto nitriles. Enzymes from the aldose reductase and the short chain dehydrogenase family displayed activity toward these substrates. All of the seven substrates were reduced with high enantioselectivities and in some cases both antipodes could be synthesized in high ees. These whole-cell reactions afforded gram quantities of asymmetric compounds that could ultimately lead to scaleable and simple synthesis to new drug analogs of serotonin reuptake inhibitors and β-adrenergic blocking agents.
- Nowill, Randall W.,Patel, Trisha J.,Beasley, David L.,Alvarez, Jose A.,Jackson III, Elizah,Hizer, Todd J.,Ghiviriga, Ion,Mateer, Scott C.,Feske, Brent D.
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supporting information; experimental part
p. 2440 - 2442
(2011/05/16)
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- Thiazolyl-Benzimidazoles
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The invention is directed to compounds of formula (1) and pharmaceutically acceptable salts thereof, methods for the preparation thereof, and methods of use thereof.
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Page/Page column 8
(2010/07/04)
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- Design, synthesis, and evaluation of 2-aryl-7-(3′,4′-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines as novel PDE-4 inhibitors
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Described herein is design, synthesis, and biological evaluation of novel series of 2-aryl-7-(3′,4′-dialkoxyphenyl)-pyrazolo[1,5-a]pyrimidines acting as inhibitors of type 4 phosphodiesterase (PDE4) which is known as a good target for the treatment of asthma and COPD. For this purpose, structure optimization was conducted with the aid of structure-based drug design using the known X-ray crystallography. Also, biological effects of these compounds on the target enzyme were evaluated by using in vitro assays, leading to the potent and selective PDE-4 inhibitor (IC50 10 nM).
- Kim, Ikyon,Song, Jong Hwan,Park, Chang Min,Jeong, Joon Won,Kim, Hyung Rae,Ha, Jin Ryul,No, Zaesung,Hyun, Young-Lan,Cho, Young Sik,Sook Kang, Nam,Jeon, Dong Ju
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scheme or table
p. 922 - 926
(2010/06/22)
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- Synthesis of 5-substituted 3-amino-1H-pyrazole-4-carbonitriles as precursors for microwave assisted regiospecific syntheses of pyrazolo[1,5-a]pyrimidines
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A simple route to 3-oxoalkanonitrile 5, a precursor of the title compounds is described. Reaction of enaminones 2 with hydroxylamine hydrochloride in ethanol yielded aldoximes 3 that were converted readily into 5 in basic medium. This method has been successfully applied with a number of substrates and resulted in excellent yields of the products. Reacting 5 with trichloroacetonitrile afforded 3-amino-2-aroyl-4,4,4-trichloro-2-butenenitriles 6 that condensed with hydrazines to yield 3-amino-1H-pyrazole-4-carbonitrile derivatives 8. Substituted pyrazolo[1,5-a]pyridmidines have been prepared with regioselective condensation reactions of 8 with nonsymmetrical dielectrophiles. The structures of compounds obtained were deduced based on 1H-NMR, 1H-15N HMBC- measurements.
- Al-Qalaf, Fawzia,Mandani, Faisal,Abdelkhalik, Mervat Mohammed,Bassam, Abeer Abdulrahman
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experimental part
p. 78 - 88
(2009/09/05)
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- Pyrolytic methods in organic synthesis: Novel routes for the synthesis of 3-oxoalkanenitriles, 2-acyl anilines, and 2-aroyl anilines
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3-Oxoalkanenitriles 1a-d were obtained in high yield by treating enaminones 6a-d with hydroxylamine hydrochloride and stirring the resulting oxime with diethyl oxalate. The formed 3-oxoalkanenitriles 1a,b readily undergo self-condensation to yield 2-aroylanilines 3a,b on heating in pyridine for eight hours or by irradiation in microwave for 1.5 minutes. In contrast, 1c-e were recovered unreacted under similar conditions. Pyrolysis of 3-aminocrotononitrile 14 produced a mixture of the aminopyridine 16, 19, and aminobenzene 22. Heating 14 in aqueous media has resulted in formation of the pyridine 20, while heating the same compound in acetic acid has afforded pyridone 20 and acetyl pyridine 24. Georg Thieme Verlag Stuttgart.
- Al-Awadi, Nouria A.,Abdelkhalik, Mervat M.,Abdelhamid, Ismail A.,Elnagdi, Mohamed H.
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p. 2979 - 2982
(2008/03/12)
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- Unexpected stereorecognition in nitrilase-catalyzed hydrolysis of β-hydroxy nitriles
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Biocatalytic enantioselective hydrolysis of β-hydroxy nitriles to corresponding (S)-enriched β-hydroxy carboxylic acids has been achieved for the first time by an isolated nitrilase bII6402 from Bradyrhizobium japonicum USDA110. This offers a new "green" approach to optically pure β-hydroxy nitriles and β-hydroxy carboxylic acids. The observed remote stereorecognition is surprising because this nitrilase shows no enantioselectivity for the hydrolysis of α-hydroxy nitriles such as mandelonitrile.
- Kamila, Sukanta,Zhu, Dunming,Biehl, Edward R.,Hua, Ling
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p. 4429 - 4431
(2007/10/03)
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- NOVEL HERBICIDES, USAGE THEREOF, NOVEL THIENOPYRIMIDINE DERIVATIVES, INTERMEDIATES OF THE SAME, AND PROCESS FOR PRODUCTION THEREOF
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A herbicide comprising, as an active ingredient, a substituted thienopyrimidine derivative represented by the formula (I): wherein all symbols are defined in the description, a method of using the same, a novel compound useful as the herbicide and a process for producing the same, and an intermediate thereof.
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Page/Page column 57
(2010/02/12)
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- Reactions of 1,3-diaryl-2-chloropropane-1,3-diones with nucleophiles - Cyanide-induced retro-Claisen-Claisen condensation
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Treatment of some 1,3-diaryl-2-chloropropane-1,3-diones, acyclic chloro-substituted enaminones and β-oxo esters with nucleophiles was shown to proceed easily with the formation, at least in the first stage, of formal nucleophilic substitution products. Treatment of enaminones and β-oxo esters with azide and cyanide ions proceeds with the preservation of the skeleton, whereas chloro-substituted diaroylmethanes undergo retro-Claisen-Claisen condensation reactions in the course of the reaction with cyanide. Dibenzoylchloromethane reacts with azide and cyanide ions with fragmentation of the molecule and subsequent reassembly, resulting in benzoylated benzaldehyde cyanohydrin and a 1,3-oxathiol derivative, respectively. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.
- Roshchupkina, Galina I.,Gatilov, Yury V.,Rybalova, Tatyana V.,Reznikov, Vladimir A.
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p. 1765 - 1773
(2007/10/03)
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- Synthesis of mono- and disubstituted 1H-imidazo[1,2-b]pyrazoles
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The improved synthesis of 1H-imidazo[1,2-b]pyrazole 1 and of mono- and disubstituted derivatives is described and representative experimental procedures are given. Namely, 2-, 3-, 7- and 6-monosubstituted (2-15k), 2,3- and 6,7-disubstituted (16,17) compounds are prepared and characterized.
- Seneci,Nicola,Inglesi,Vanotti,Resnati
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p. 311 - 341
(2007/10/03)
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- Steric and electronic control in the addition of hydrazine and phenylhydrazine to α-[(dimethylamino)methylene]-β-oxoarylpropanenitriles
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Reaction of hydrazine with α-[(dimethylamino)methylene]-β-oxoarylpropanenitriles 2 gives a mixture of the 4-aroyl-5-aminopyrazoles 3 and the 5-aryl-4-cyanopyrazoles 4. Similarly reaction of 2 with phenylhydrazine gives rise to the 5-amino-4-aroyl-1-phenylpyrazoles 5 and 5-aryl-4-cyano-1-phenylpyrazoles 6. The regioselectivity of addition has been investigated with respect to the electronic nature and steric requirements of the aromatic substitution. The ratio of products was found to be independent of the electronic nature of the substituent. The outcome of the reaction was however very sensitive to steric factors. Substituents in the para- and meta-positions favoured formation of the pyrazole-nitrile products 4 and 6, whereas sterically demanding ortho-substituents favoured the pyrazole-amino ketones 3 and 5.
- Tupper, David E.,Bray, Mark R.
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p. 337 - 341
(2007/10/03)
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- Novel alpha-cyano-beta-oxopropionamides
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α-(Substituted carbamoyl)-β-aryl- and heteroaryl-β-oxo-propionitriles of formula, , A-CO- enol ethers thereof and salts thereof, as well as pharmaceutical preparations containing same and methods of preparing and using these compounds are disclosed. Said compounds represent novel antiinflammatory and antirheumatic agents. Their property to interfere with both the cyclooxygenase and lipoxygenase pathway of the arachidonic fatty acid bioconversion to inflammatory mediators make them valuable therapeutics. These properties render the mentioned substituted carbamoyl-β-oxopropionitriles useful for the treatment of arthritic and rheumatic diseases and other inflammatory conditions in mammals.
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- Heteroaryl 3-oxo-propanenitrile derivatives, pharmaceutical compositions and use
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The invention relates to compounds having the general formula (I) STR1 and the pharmaceutically acceptable salts thereof, which possess immunomodulating activity and are useful e.g. in the treatment of neoplastic diseases and acute and chronic infections of both bacterial and viral origin in mammals.
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- Studies on β-Enaminonitriles: Part I- Benzoylation in Presence of Sodium in Benzene
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Sodium dust in benzene brings about an unusual reductive decyanation of β-aminocrotononitrile (1) to afford N-benzoylisopropylamine (2) as the major product, for which a tentative mechanism involving radical addition has been suggested.Benzoylation of β-aryl-β-aminoacrylonitriles (10, 11 and 12), however, under somilar conditions furnish a complex mixture of compounds, namely, β-aryl-β-amino-α-benzoylacrylonitriles (14, 18 and 22), pyrimidines (13, 17 and 21), β-ketonitriles (19, 20 and 23) and benzamide (16) in varying yields but in no case the formation of the corresponding reductive decyanation products have been observed.
- Sarkar, Mili,Chattopadhyay, S.,Mahalanabis, Kumar K.
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p. 1133 - 1137
(2007/10/02)
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