- 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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- Synthesis and in vivo evaluation of a novel peripheral benzodiazepine receptor PET radioligand
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The novel pyrazolopyrimidine ligand, N,N-diethyl-2-[2-(4-methoxyphenyl)-5, 7-dimethyl-pyrazolo[1,5-a]pyrimidin-3-yl]-acetamide 1 (DPA-713), has been reported as a potent ligand for the peripheral benzodiazepine receptor (PBR) displaying an affinity of Ks
- James, Michelle L.,Fulton, Roger R.,Henderson, David J.,Eberl, Stefan,Meikle, Steven R.,Thomson, Sally,Allan, Robin D.,Dolle, Frederic,Fulham, Michael J.,Kassiou, Michael
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- Mechanistic selectivity investigation and 2D-QSAR study of some new antiproliferative pyrazoles and pyrazolopyridines as potential CDK2 inhibitors
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Novel series of diphenyl-1H-pyrazoles (4a-g) and pyrazolo[3,4-b]pyridines (5a-g and 7a-i) were synthesized and evaluated for their antiproliferative activity against breast cancer cell line (MCF7) and Hepatocellular carcinoma cell line (HepG2). The highest MCF7 growth inhibition activity was attained via compounds 4f and 7e (IC50 = 1.29 and 0.93 μM, respectively), while compounds 5b and 7f were the most active ones against HepG2 (IC50 = 1.57 and 1.33 μM, respectively) compared to doxorubicin (IC50 = 1.88 and 7.30 μM, respectively). Cell cycle analysis showed arrest at S and G2-M phases in MCF7 cells treated with 4f and 7e, and at G2-M and G1/S phases in HepG2 cells treated with 5b and 7f, respectively. Apoptotic effect of compounds 4f, 5b, 7e, and 7f was indicated via their pre-G1 early and late apoptotic effects and augmented levels of caspase-9/MCF7 and caspase-3/HepG2. A worthy safety profile was assessed for compounds 4f and 7e on MCF10A and compounds 5b and 7f on THLE2 treated normal cells. Furthermore, compounds 4f, 5b and 7f displayed a promising selective profile for CDK2 inhibition vs. CDK1, CDK4, and CDK7 isoforms as proved from their selectivity index. Docking in CDK2 ATP binding site, co-crystallized with R-Roscovitine, demonstrated analogous interactions and comparable binding energy with the native ligand. 2D QSAR sighted the possible structural features governing the CDK2 inhibition activity elicited by the studied pyrazolo[3,4-b]pyridines. These findings present compounds 4f, 5b, and 7f as selective CDK2 inhibitors with promising antiproliferative activity against MCF7 and HepG2 cancer cells.
- Hassan, Ghaneya S.,Georgey, Hanan H.,Mohammed, Esraa Z.,George, Riham F.,Mahmoud, Walaa R.,Omar, Farghaly A.
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- 3,5-Diaryl-1H-pyrazolo[3,4-b]pyridines as potent tubulin polymerization inhibitors: Rational design, synthesis and biological evaluation
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A series of novel 3,5-diaryl-1H-pyrazolo[3,4-b]pyridines as tubulin polymerization inhibitors targeting the colchicine site were designed via ring tethering strategy, which was supported by conformational analysis. The general, chemically unstable and rot
- Zhai, Min'an,Liu, Shiyuan,Gao, Meiqi,Wang, Long,Sun, Jun,Du, Jianan,Guan, Qi,Bao, Kai,Zuo, Daiying,Wu, Yingliang,Zhang, Weige
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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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- 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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- Asymmetric Hydroacylation Involving Alkene Isomerization for the Construction of C3-Chirogenic Center
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A new transformation pattern for enantioselective intramolecular hydroacylation has been developed involving an alkene isomerization strategy. Proceeding through a five-membered rhodacycle intermediate, 3-enals were converted to C3- or C3,C5-chirogenic cyclopentanones with satisfactory yields, diastereoselectivities, and enantioselectivities. A catalytic cycle has been theoretically calculated and the origin of the stereoselection is rationally explained.
- Liu, Chong,Yuan, Jing,Zhang, Zhenfeng,Gridnev, Ilya D.,Zhang, Wanbin
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supporting information
p. 8997 - 9002
(2021/03/16)
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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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- 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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- HIGHLY POTENT TACC3 INHIBITOR AS A NOVEL ANTICANCER DRUG CANDIDATE
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The present invention relates to a new inhibitor chemotype 3-(4-methoxyphenyl)-N-(2-morpholinopyrimidin-4-yl) isoxazol-5-amine (BO-264) targeting TACC3 protein with high potency as a mitotic blocker for the treatment of breast and potentially other cancers.
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Page/Page column 12
(2020/02/14)
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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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- 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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- Tricyclic heterocycles display diverse sensitivity to the A147T TSPO polymorphism
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The 18 kDa translocator protein (TSPO) is a target for the development of imaging agents to detect neuroinflammation. The clinical utility of second-generation TSPO ligands has been hindered by the presence of a polymorphism, rs6971, which causes a non-co
- Sokias, Renee,Werry, Eryn L.,Alison Cheng, Hei Wun,Lloyd, James H.,Sohler, Greta,Danon, Jonathan J.,Montgomery, Andrew P.,Du, Jonathan J.,Gao, Quanqing,Hibbs, David E.,Ittner, Lars M.,Reekie, Tristan A.,Kassiou, Michael
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- Discovery of 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4: Biological evaluation and docking studies
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In this study, novel 2,4-diaminopyrimidine derivatives targeting p21-activated kinase 4 (PAK4) were discovered and evaluated for their biological activity against PAK4. Among the derivatives studied, promising compounds A2, B6, and B8 displayed the highest inhibitory activities against PAK4 (IC50 = 18.4, 5.9, and 20.4 nM, respectively). From the cellular assay, compound B6 exhibited the highest potency with an IC50 value of 2.533 μM against A549 cells. Some compounds were selected for computational ADME (absorption, distribution, metabolism, and elimination) properties and molecular docking studies against PAK4. The detailed structure–activity relationship based on the biochemical activities and molecular docking studies were explored. According to the docking studies, compound B6 had the lowest docking score (docking energy: ?7.593 kcal/mol). The molecular docking simulation indicated the binding mode between compound B6 and PAK4. All these results suggest compound B6 as a useful candidate for the development of a PAK4 inhibitor.
- Qin, Qiaohua,Wu, Tianxiao,Yin, Wenbo,Sun, Yixiang,Zhang, Xiangyu,Wang, Ruifeng,Guo, Jing,Zhao, Dongmei,Cheng, Maosheng
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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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- Reaction of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via Intramolecular N-O Bond Formation
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An efficient new synthesis of 3,5-bis(het)arylisoxazoles, involving the reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium azide in the presence of IBX catalyst, has been reported. The reaction proceeds at room temperature in high yields and is applicable to a broad range of substrates including the synthesis of 5-methyl-3-arylisoxazoles, a key subunit present in several β-lactamase-resistant antibiotics. A probable mechanism for the formation of isoxazoles has been suggested. A few of the 5-styryl/arylbutadienyl-3-(het)arylisoxazoles have also been synthesized by reacting the corresponding 1-(het)aryl-1-(methylthio)-4-(het)arylidene-but-1-en-3-ones with sodium azide at higher temperatures. The reaction of β-ketodithioesters with sodium azide is shown to furnish β-ketonitriles in good yields.
- Antony P, Mary,Balaji, Gantala L.,Iniyavan, Pethaperumal,Ila, Hiriyakkanavar
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p. 15422 - 15436
(2020/11/30)
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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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- Imidazolium-Based Ionic Network as a Robust Heterogeneous Catalyst in Synthesis of Phenacyl Derivatives
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A new imidazolium-based poly(ionic liquid) has been synthesized and used as a robust heterogeneous catalyst for the preparation of phenacyl derivatives by an SN2 reaction of different phenacyl bromides with a broad range of nucleophiles. The products are obtained in high yields under mild conditions. The catalyst can be recycled efficiently.
- Kakesh,Sayyahi,Badri,Tahanpesar
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p. 1218 - 1220
(2019/07/16)
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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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- Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2-Aminothiazoles
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3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated α-arylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21 examples) was assembled by a sequence employing Suzuki coupling of newly prepared, properly protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.
- Havel, Stepan,Khirsariya, Prashant,Akavaram, Naresh,Paruch, Kamil,Carbain, Benoit
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p. 15380 - 15405
(2019/01/04)
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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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supporting information
p. 574 - 577
(2017/01/16)
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- Catalytic Enantioselective Synthesis of Highly Functionalized Difluoromethylated Cyclopropanes
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The first catalytic asymmetric synthesis of highly functionalized difluoromethylated cyclopropanes is described. The method, based on a rhodium-catalyzed cyclopropanation of difluoromethylated olefins, gives access to a broad range of cyclopropanes bearing ester, ketone, or nitro functional groups. By using Rh2((S)-BTPCP)4 as a catalyst, the corresponding products were obtained in high yields and high diastereo- and enantioselectivities (up 20:1 d.r. and 99 % ee). This methodology allowed preparation of enantioenriched difluoromethylcyclopropanes for the first time.
- Bos, Maxence,Huang, Wei-Sheng,Poisson, Thomas,Pannecoucke, Xavier,Charette, André B.,Jubault, Philippe
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supporting information
p. 13319 - 13323
(2017/10/17)
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- SeO2-Mediated One-Pot Synthesis of 3-Cyanofurans from 3-Oxo-3-arylpropanenitriles and Substituted Acetaldehydes
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An SeO2-mediated one-pot method was established for the synthesis of 3-cyanofurans from 3-oxo-3-arylpropanenitriles and substituted acetaldehydes. The generality of the reaction was explored, and a plausible mechanism is proposed.
- Zhou, Jie,Zhu, Xinhai,Huang, Manna,Wan, Yiqian
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supporting information
p. 2317 - 2321
(2017/05/01)
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- Novel ligand SXH 1001 of transport protein TSPO, 18kDa as well as preparation method and application of novel ligand
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The invention relates to a novel ligand SXH 1001 of a transport protein TSPO, 18kDa as well as a preparation method and application of the novel ligand. The novel ligand is prepared by the following steps: synthesizing 4-methoxy benzoyl acetonitrile, namely dissolving 4-methoxy methyl benzoate in anhydrous acetonitrile, adding sodium methylate, performing a reflux reaction, performing vacuum evaporation to eliminate a solvent, adding water and ethyl acetate into residues, performing stirring fully, separating a water layer, adjusting the pH value to 8 with concentrated hydrochloric acid, performing extraction with ethyl acetate, and drying an organic layer with anhydrous sodium sulfate, and performing concentration and column chromatography to obtain a nearly white solid product 1 containing 4-methoxy benzoyl acetonitrile; synthesizing an intermediate product 2; synthesizing an intermediate product 3; synthesizing an intermediate product 4; synthesizing a final product 6. The application is that a molecular imaging probe for PET development is prepared by using 11C or 18F markers. The novel ligand has the advantages of high yield, high blood brain barrier pass rate, small noise and clear images.
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Paragraph 0110; 0117
(2017/07/21)
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- Catalytic Activation of 1-Cyano-3,3-dimethyl-3-(1H)-1,2-benziodoxole with B(C6F5)3 Enabling the Electrophilic Cyanation of Silyl Enol Ethers
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The Lewis acidic activation of a hypervalent iodine reagent containing a transferable cyano group, 1-cyano-3,3-dimethyl-3-(1H)-1,2-benziodoxole (CDBX), with B(C6F5)3, to achieve the catalytic electrophilic cyanation of silyl enol ethers is presented. Mechanistic studies indicate that CDBX is activated through coordination of its cyano group to B(C6F5)3, thus enabling the electrophilic cyanation reaction to occur.
- Nagata, Takaya,Matsubara, Hiroki,Kiyokawa, Kensuke,Minakata, Satoshi
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supporting information
p. 4672 - 4675
(2017/09/12)
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- Fragment-Based Approaches to the Development of Mycobacterium tuberculosis CYP121 Inhibitors
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The essential enzyme CYP121 is a target for drug development against antibiotic resistant strains of Mycobacterium tuberculosis. A triazol-1-yl phenol fragment 1 was identified to bind to CYP121 using a cascade of biophysical assays. Synthetic merging and optimization of 1 produced a 100-fold improvement in binding affinity, yielding lead compound 2 (KD = 15 μM). Deconstruction of 2 into its component retrofragments allowed the group efficiency of structural motifs to be assessed, the identification of more LE scaffolds for optimization and highlighted binding affinity hotspots. Structure-guided addition of a metal-binding pharmacophore onto LE retrofragment scaffolds produced low nanomolar (KD = 15 nM) CYP121 ligands. Elaboration of these compounds to target binding hotspots in the distal active site afforded compounds with excellent selectivity against human drug-metabolizing P450s. Analysis of the factors governing ligand potency and selectivity using X-ray crystallography, UV-vis spectroscopy, and native mass spectrometry provides insight for subsequent drug development.
- Kavanagh, Madeline E.,Coyne, Anthony G.,McLean, Kirsty J.,James, Guy G.,Levy, Colin W.,Marino, Leonardo B.,De Carvalho, Luiz Pedro S.,Chan, Daniel S. H.,Hudson, Sean A.,Surade, Sachin,Leys, David,Munro, Andrew W.,Abell, Chris
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p. 3272 - 3302
(2016/05/19)
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- Synthesis method of 2-methyl-3,4-binitro-5-(methoxyphenyl) pyrazole
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The invention relates to 2-methyl-3,4-binitro-5-(methoxyphenyl) pyrazole, and belongs to the field of chemical synthesis. By aiming at the problems that the conventional pyrazole compound containing nitryl and benzene rings has poor heat stability and can be easily thermally decomposed, the method adopts the technical scheme that methyl p-methoxybenzoate and methylbenzene are subjected to water bath heating to take reaction with sodium hydride; meanwhile, acetonitrile is dripped for preparing 3-carbonyl-p-methoxyphenyl propionitrile; then, through the reaction of the glacial acetic acid, the iodine and the sulfuric acid solution containing iodic acid, 1-methyl-3,4,5-tniodide pyrazole is prepared; then, the 1-methyl-3,4,5-tniodide pyrazole is subjected to nitrification to prepare 1-methyl-3,4,5-trinitro pyrazole; finally, the 1-methyl-3,4,5-trinitro pyrazole and the 3-methyl-3,4-binitro-5-(methoxyphenyl) pyrazole are subjected to water bath heating reaction; the 2-methyl-3,4-binitro-5-(methoxyphenyl) pyrazole is prepared and obtained through thin layer chromatographic reaction detection. Compared with an ordinary pyrazole compound containing nitryl and benzene rings, the 2-methyl-3,4-binitro-5-(methoxyphenyl) pyrazole has the advantage that the thermal stability is improved by 50 to 60 percent.
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Paragraph 0005; 0008
(2016/12/01)
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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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- Integration of aqueous biphasic with magnetically recyclable systems: Polyethylene glycol-grafted Fe3O4 nanoparticles catalyzed phenacyl synthesis in water
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The present work trends to define an efficient phenacyl catalytic synthesis method employing a new nano-magnetite-supported organocatalyst. Polyethylene glycol (PEG) was bonded successfully onto silica coated ferrite and the resultant nanoparticles (PEG@SiO2@Fe3O4) characterized by fourier transform infrared spectroscopy (FT-IR), atomic force microscopy (AFM), thermal gravimetric analysis (TGA), vibrating sample magnetometry (VSM), energy dispersive X-ray analysis (EDAX) and X-ray diffraction (XRD) that exhibited a good catalytic activity in the reaction. The nanoparticles could be easily separated from the reaction mixture by an external magnet and reused in seven reaction cycles without significant loss of activity.
- Amini, Atefeh,Sayyahi, Soheil,Saghanezhad, Seyyed Jafar,Taheri, Narges
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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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- 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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- 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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- Chemoselective efficient synthesis of functionalized β-oxonitriles through cyanomethylation of Weinreb amides
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A synthesis of β-oxonitriles is reported via the generation of R1R2CLiCN species followed by the trapping with variously decorated Weinreb amides. The optimization study revealed that lithiation of acetonitriles is best accomplished by deprotonation with MeLi-LiBr at low temperature. The protocol can be conveniently adapted to the synthesis of α-mono or α,α-disubstituted cyanoketones. 15N- and 17O-NMR data are reported for selected compounds. This journal is
- Mamuye, Ashenafi Damtew,Castoldi, Laura,Azzena, Ugo,Holzer, Wolfgang,Pace, Vittorio
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supporting information
p. 1969 - 1973
(2015/03/05)
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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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- 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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- 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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- 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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- 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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supporting information
p. 45 - 52
(2013/03/13)
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- Synthesis and biological evaluation of bifendate-chalcone hybrids as a new class of potential P-glycoprotein inhibitors
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Overexpression of P-glycoprotein (P-gp) is one of the major problems to successful cancer chemotherapy. To find novel effective P-gp inhibitors, a series of bifendate-chalcone hybrids were synthesized and evaluated. Among them, the most active compound 8g
- Gu, Xiaoke,Ren, Zhiguang,Tang, Xiaobo,Peng, Hui,Ma, Yuanfang,Lai, Yisheng,Peng, Sixun,Zhang, Yihua
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experimental part
p. 2540 - 2548
(2012/05/31)
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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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- Tandem cross-Rauhut-Currier/cyclization reactions of activated alkenes to give densely functionalized 3,4-dihydropyrans
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A novel tandem cross-Rauhut-Currier/cyclization reaction between α,β-unsaturated ketones was developed. Using DABCO (20 mol %) as the catalyst, a series of densely functionalized 3,4-dihydropyrans were obtained in excellent yields and stereoselectivities (up to 98% yield, >99:1 dr). A tentative catalytic cycle was proposed with key intermediates confirmed by ESIMS studies.
- Liu, Wen,Zhou, Jing,Zheng, Changwu,Chen, Xingkuan,Xiao, Hua,Yang, Yingquan,Guo, Yinlong,Zhao, Gang
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supporting information; experimental part
p. 1768 - 1773
(2011/04/15)
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- Iridium diamine catalyst for the asymmetric transfer hydrogenation of ketones
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A simple and very efficient chiral aqua iridium(III) diamine complex leads to excellent enantioselectivities in the asymmetric transfer hydrogenation of various α-cyano and α-nitro ketones. The catalyst provides the ortho-substituted aromatic alcohols with especially high ee values. The diamine ligands can be used directly as chiral ligands; conversion into the corresponding sulfamide is not necessary.
- Vazquez-Villa, Henar,Reber, Stefan,Ariger, Martin A.,Carreira, Erick M.
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supporting information; experimental part
p. 8979 - 8981
(2011/11/30)
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- Synthesis of novel twisted heterocyclic analogues of s-indacenes
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A series of novel compounds as candidates for OLED applications were synthesized by cyclization reactions of neighbouring rings in dipyrazolo[3,4-b:4',3'-e]pyridines 8-12. The desymmetrization of these molecules leading to 14 can be performed using both KOH/isoquinoline or palladium catalysts. The resulting structures contain a helical arrangement of four different rings. ARKAT-USA, Inc.
- Danel, Krzysztof S.,Uchacz, Tomasz,Karelus, Marcin
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scheme or table
p. 272 - 280
(2011/08/21)
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- An efficient method for synthesis of phenacyl derivatives under homogeneous phase transfer catalyst condition in aqueous media
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In this letter, a mild and efficient procedure for synthesis of phenacyl derivatives under homogenous catalysis in the presence of tetrabutylammonium bromide in aqueous media is described. The nucleophilic substitution reactions were performed under ecofriendly conditions and gave the corresponding products in high yields and short reaction times.
- Sayyahi, Soheil,Saghanezhad, Jafar
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experimental part
p. 300 - 302
(2012/01/14)
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- Radical cyclizations of conjugated esters and amides with 3-oxopropanenitriles mediated by manganese(III) acetate
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Radical cyclizations of conjugated esters and amides with 3-oxopropanenitriles in presence of manganese(III) acetate produced ethyl 4-cyano-2,3-dihydrofuran-3-carboxylates and 4-cyano-2,3-dihydrofuran-3- carboxamides in good yields. The radical cyclizations of conjugated amides gave 2,3-dihydrofurans in better yields than that of conjugated esters. Moreover, the reactions of thienyl substituted amides and esters with 3-oxopropanenitriles afforded 2,3-dihydrofurans more efficiently than phenyl substituted ones. ARKAT-USA, Inc.
- Yilmaz, E. Vildan Burgaz,Yilmaz, Mehmet,Oektemer, Atilla
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body text
p. 363 - 376
(2011/09/20)
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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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- 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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- Pyrazolo[1,5-a]pyrimidine acetamides: 4-Phenyl alkyl ether derivatives as potent ligands for the 18 kDa translocator protein (TSPO)
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Herein, we report the synthesis of four new phenyl alkyl ether derivatives (7, 9-11) of the pyrazolo[1,5-a]pyrimidine acetamide class, all of which showed high binding affinity and selectivity for the TSPO and, in the case of the propyl, propargyl, and bu
- Reynolds, Aaron,Hanani, Raphy,Hibbs, David,Damont, Annelaure,Pozzo, Eleonora Da,Selleri, Silvia,Dollé, Frédéric,Martini, Claudia,Kassiou, Michael
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supporting information; experimental part
p. 5799 - 5802
(2011/01/05)
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- COMPOUND FORMS AND USES THEREOF
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The present invention provides, among other things, forms of a compound of formula 1. In some embodiments, the present invention provides salt forms and/or crystal forms. In some embodiments, the present invention provides solid forms. The present inventi
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Page/Page column 13
(2009/07/25)
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- SYNTHESIS OF PYRAZOLES
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The present invention provides methods of making HCl salts, and methods of using them to modulate alpha7 nicotinic acetylcholine receptors and/or to treat any of a variety of disorders, diseases, and conditions. Provided compounds can affect, among other
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Page/Page column 62-63
(2009/08/16)
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