- Synthesis of Some 1,4,6-Trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles and Their Biological Evaluation as Cytotoxic and Antimicrobial Agents
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A series of novel 1,4,6-trisubstituted-2-oxo-1,2-dihydropyridine-3-carbonitriles supported with some functionalities reported to contribute to significant chemotherapeutic potential were synthesized and evaluated for their antimicrobial and/or cytotoxic activities. Thirteen compounds exhibited cytotoxic potential against a panel of three human tumor cell lines. Compounds 15, 23, and 24 proved to be the most active agents with a broad spectrum of cytotoxic activity. Analog 24 was considered as the most active cytotoxic agent, being 2.5 times more active than doxorubicin against the colon HT29 carcinoma cell line. Seventeen compounds were able to exert a variable antimicrobial profile, among which analogs 15, 20, 21, 23, and 24 were prominently active. The highest antimicrobial potential was displayed by analog 24, being equipotent to ampicillin against Staphylococcus aureus and Escherichia coli, together with a considerable antifungal activity comparable with clotrimazole. Collectively, compounds 15, 23, and 24 could be considered as possible dual antimicrobial-anticancer candidates. Novel substituted 2-oxo-1,2-dihydropyridine-3-carbonitriles (A, B) and some derived 1,2,4-triazolo[4,3-a]-pyridinones (C) were synthesized and evaluated for their antimicrobial and cytotoxic activities. Three analogs are possible dual antimicrobial-anticancer candidates.
- Faidallah, Hassan M.,Rostom, Sherif A. F.,Badr, Mona H.,Ismail, Azza E.,Almohammadi, Ameen M.
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- Synthesis and biological evaluation of new pyrazolebenzene-sulphonamides as potential anticancer agents and hCA I and II inhibitors
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Cancer is a disease characterized by the continuous growth of cells without adherence to the rules that healthy normal cells obey. Carbonic anhydrase I and II (CA I and CA II) inhibitors are used for the treatment of some diseases. The available drugs in the market have limitations or side effects, which bring about the need to develop new drug candidate compound(s) to overcome the problems at issue. In this study, new pyrazole-sulphonamide hybrid compounds 4-[5-(1,3-benzodioxol-5-yl)-3-aryl-4,5-dihydro-1Hpyrazol- 1-yl]benzenesulphonamides (4a - 4j) were designed to discover new drug candidate compounds. The compounds 4a - 4j were synthesized and their chemical structures were confirmed using spectral techniques. The hypothesis tested was whether an introduction of methoxy and polymethoxy group(s) lead to an increased potency selectivity expression (PSE) value of the compound, which reflects cytotoxicity and selectivity of the compounds. The cytotoxicity of the compounds towards tumor cell lines were in the range of 6.7 - 400 μM. The compounds 4i (PSE2 = 461.5) and 4g (PSE1 = 193.2) had the highest PSE values in cytotoxicity assays. Ki values of the compounds were in the range of 59.8 ± 3.0 - 12.7 ± 1.7 nM towards hCA I and in the range of 24.1 ± 7.1 - 6.9 ± 1.5 nM towards hCA II. While the compounds 4b, 4f, 4g, and 4i showed promising cytotoxic effects, the compounds 4c and 4g had the inhibitory potency towards hCA I and hCA II, respectively. These compounds can be considered as lead compounds for further research.
- GUL, Halise Inci,GULCIN, Ilhami,KAYA, Ruya,SAKAGAMI, Hiroshi,TUGRAK, Mehtap
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p. 528 - 539
(2021/07/26)
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- Structural elucidation, bio-inspired synthesis, and biological activities of cyclic diarylpropanes from Horsfieldia kingii
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Bioactivity-guided phytochemical investigation on 70% aqueous acetone extracts of the twigs and leaves of Horsfieldia kingii led to the isolation of two novel cyclic diarylpropanes (1 and 2) bearing a 2,3-dihydro-1H-indene core, one new diarylpropane (3), six known diarylpropanes (4–9), one flavanol (10), and seven lignans (11–17). Their structures were determined by extensive spectroscopic analysis, electronic circular dichroism calculations, and X-ray diffraction crystallography. Moreover, a biomimetic synthesis of 1 and 2 were accomplished in four steps. The in vitro nitric oxide production inhibition tests of these compounds revealed that compounds (±)-2, (+)-2, (?)-2, and 10 were potential with IC50 values lower than 10 μM. Compound 2 could inhibit iNOS expression in LPS-induced RAW264.7 cells at a series of non-cytotoxic concentrations (20 μM). Furthermore, the bioassay results also suggested the primary SARs of 1-phenyl-2,3-dihydro-1H-indene based scaffold.
- Chen, Lei,Chen, Ye-Gao,Li, Dashan,Liu, Yuan-Lie,Shao, Li-Dong,Wang, Wen-Jing,Xie, Xiao-Yan,Zhan, Rui
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supporting information
(2020/09/02)
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- Discovery of new fluorescent thiazole–pyrazoline derivatives as autophagy inducers by inhibiting mTOR activity in A549 human lung cancer cells
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A series of fluorescent thiazole–pyrazoline derivatives was synthesized and their structures were characterized by 1H NMR, 13C NMR, and HRMS. Biological evaluation demonstrated that these compounds could effectively inhibit the growt
- Chen, Yuan,Gao, DongFang,Kong, Feng,Lin, YuXing,Lin, ZhaoMin,Miao, JunYing,Wang, Peng,Wang, ZhaoYang,Zhang, Lu,Zhang, Ming,Zhao, BaoXiang,Zhou, XueWen
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- The synthesis of 4,6-diaryl-2-pyridones and their bioactivation in CYP1 expressing breast cancer cells
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As part of a programme to develop anticancer prodrugs which are activated by cytochrome P450 (CYP)1B1, a library of 4,6-diaryl-2-pyridones was synthesised in yields of 6–60% from the corresponding chalcones. A number of these derivatives showed promising antiproliferative activities in human breast cancer cell lines which express CYP1B1 and CYP1A1, while showing little toxicity towards a non-tumour breast cell line with no CYP expression. Metabolism studies provided evidence supporting the involvement of CYP1 enzymes in the bioactivation of these compounds.
- Ruparelia, Ketan C.,Lodhi, Sabahat,Ankrett, Dyan N.,Wilsher, Nicola E.,Arroo, Randolph R.J.,Potter, Gerard A.,Beresford, Kenneth J.M.
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p. 1403 - 1406
(2019/04/01)
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- Design, synthesis and biological evaluation of novel pyrazoline-containing derivatives as potential tubulin assembling inhibitors
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Abstract A series of novel pyrazoline-containing derivatives (15-47) has been designed, synthesized and evaluated for their biological activities. Among them, compound 18 displayed the most potent antiproliferative activity against A549, MCF-7 and HepG-2 cells line (IC50 Combining double low line 0.07 μM, 0.05 μM, 0.03 μM, respectively) and the tubulin polymerization inhibitory activity (IC50 Combining double low line 1.88 μM), being comparable to CA-4. Furthermore, we also tested that compound 18 was a potent inducer of apoptosis in HepG-2 cells and it had cellular effects typical for microtubule interacting agents, causing accumulation of cells in the G2/M phase of the cell cycle. These studies, along with molecular docking, provided a new molecular scaffold for the further development of antitumor agents that target tubulin.
- Qin, Ya-Juan,Li, Yu-jing,Jiang, Ai-Qin,Yang, Meng-Ru,Zhu, Qi-Zhang,Dong, Hong,Zhu, Hai-Liang
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p. 447 - 457
(2015/04/14)
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- Asymmetric total syntheses of megacerotonic acid and shimobashiric acid A
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The asymmetric total syntheses of the α-benzylidene-γ-butyrolactone natural products megacerotonic acid and shimobashiric acid A have been accomplished in nine and 11 steps, respectively, from simple, commercially available starting materials. The key step for each synthesis is the (arene)RuCl(monosulfonamide)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of racemic α,δ-diketo-β-aryl esters to establish the absolute stereochemistry. Intramolecular diastereoselective Dieckmann cyclization forms the lactone core, and ketone reduction/alcohol elimination installs the α-arylidene.
- Krabbe, Scott W.,Johnson, Jeffrey S.
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supporting information
p. 1188 - 1191
(2015/03/14)
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- Antimycobacterial and anti-inflammatory activities of substituted chalcones focusing on an anti-tuberculosis dual treatment approach
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Tuberculosis (TB) remains a serious public health problem aggravated by the emergence of M. tuberculosis (Mtb) strains resistant to multiple drugs (MDR). Delay in TB treatment, common in the MDR-TB cases, can lead to deleterious life-threatening inflammation in susceptible hyper-reactive individuals, encouraging the discovery of new anti-Mtb drugs and the use of adjunctive therapy based on anti-inflammatory interventions. In this study, a series of forty synthetic chalcones was evaluated in vitro for their anti-inflammatory and antimycobacterial properties and in silico for pharmacokinetic parameters. Seven compounds strongly inhibited NO and PGE2 production by LPS-stimulated macrophages through the specific inhibition of iNOS and COX-2 expression, respectively, with compounds 4 and 5 standing out in this respect. Four of the seven most active compounds were able to inhibit production of TNF-α and IL-1β. Chalcones that were not toxic to cultured macrophages were tested for antimycobacterial activity. Eight compounds were able to inhibit growth of the M. bovis BCG and Mtb H37Rv strains in bacterial cultures and in infected macrophages. Four of them, including compounds 4 and 5, were active against a hypervirulent clinical Mtb isolate as well. In silico analysis of ADMET properties showed that the evaluated chalcones displayed satisfactory pharmacokinetic parameters. In conclusion, the obtained data demonstrate that at least two of the studied chalcones, compounds 4 and 5, are promising antimycobacterial and anti-inflammatory agents, especially focusing on an anti-tuberculosis dual treatment approach.
- Ventura, Thatiana Lopes Biá,Calixto, Sanderson Dias,De Azevedo Abrahim-Vieira, Bárbara,De Souza, Alessandra Mendon?a Teles,Mello, Marcos Vinícius Palmeira,Rodrigues, Carlos Rangel,De Mariz E Miranda, Leandro Soter,De Souza, Rodrigo Octavio Mendon?a Alves,Leal, Ivana Correa Ramos,Lasunskaia, Elena B.,Muzitano, Michelle Fraz?o
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p. 8072 - 8093
(2015/05/20)
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- 4,5-Dihydropyrazole derivatives containing oxygen-bearing heterocycles as potential telomerase inhibitors with anticancer activity
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Telomere and telomerase were closely related to the occurrence and development of some cancers. After the key active site of telomerase was identified, to enhance the ability of dihydropyrazole derivatives to inhibit telomerase, we designed a series of novel 4,5-dihydropyrazole derivatives containing heterocyclic oxygen moiety based on previous studies. The telomerase inhibition assay showed that compound 10a displayed the most potent inhibitory activity with an IC50 value of 0.6 μM for telomerase. The antiproliferative assay showed that 10a exhibited high activity against human gastric cancer cell SGC-7901 with an IC50 value of 10.95 ± 0.60 μM. Flow cytometric analysis and western blot results showed that 10a induced both apoptosis and autophagy. A docking simulation showed that 10a could bind well to the active site of telomerase and act as a telomerase inhibitor. The 3D-QSAR model was also built to provide a more pharmacological understanding that could be used to design new agents with more potent telomerase inhibitory activity.
- Luo, Yin,Zhou, Yang,Fu, Jie,Zhu, Hai-Liang
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p. 23904 - 23913
(2014/07/07)
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- One-pot synthesis of multifunctionalized cyclopropanes
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A facile one-step synthetic protocol toward multifunctionalized cyclopropanes 4 is developed from substituted chalcones 1 and sulfones 2 in good yields via a [2C+1C] annulation.
- Chang, Meng-Yang,Chen, Yi-Chia,Chan, Chieh-Kai
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p. 2257 - 2263
(2014/03/21)
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- Synthesis, molecular docking and evaluation of thiazolyl-pyrazoline derivatives containing benzodioxole as potential anticancer agents
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A series of novel thiazolyl-pyrazoline derivatives containing benzodioxole (C1-C20) have been designed and synthesized. Among of the synthesized compounds, 2-(5-(benzo[d][1,3]dioxol-5-yl)-3-(4-bromophenyl)-4,5-dihydro-1H-pyrazol-1-yl)- 4-(4-bromophenyl)thiazole (C6) displayed the most potent inhibitory activity for HER-2 (IC50 = 0.18 μM for HER-2). Antiproliferative assay results indicated that compound C6 owned high antiproliferative activity against MCF-7 and B16-F10 in vitro, with IC50 value of 0.09 and 0.12 μM, respectively, being comparable with the positive control Erlotinib. Docking simulation was further performed to determine the probable binding model. Based on the preliminary results, compound C6 with potent inhibitory activity in tumor growth would be a potential anticancer agent.
- Wang, Hai-Hong,Qiu, Ke-Ming,Cui, Hong-En,Yang, Yu-Shun,Yin-Luo,Xing, Man,Qiu, Xiao-Yang,Bai, Li-Fei,Zhu, Hai-Liang
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p. 448 - 455
(2013/02/25)
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- Synthesis, biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole derivatives as telomerase inhibitors
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A series of novel aryl-2H-pyrazole derivatives bearing 1,4-benzodioxan or 1,3-benzodioxole moiety were designed as potential telomerase inhibitors to enhance the ability of aryl-2H-pyrazole derivatives to inhibit telomerase, a target of anticancer. The telomerase inhibition tests showed that compound 16A displayed the most potent inhibitory activity with IC50 value of 0.9 μM for telomerase. The antiproliferative tests showed that compound 16A exhibited high activity against human gastric cancer cell SGC-7901 and human melanoma cell B16-F10 with IC50 values of 18.07 and 5.34 μM, respectively. Docking simulation showed that compound 16A could bind well with the telomerase active site and act as telomerase inhibitor. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity.
- Luo, Yin,Zhang, Shuai,Qiu, Ke-Ming,Liu, Zhi-Jun,Yang, Yu-Shun,Fu, Jie,Zhong, Wei-Qing,Zhu, Hai-Liang
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p. 1091 - 1095
(2013/03/13)
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- One-pot synthesis of multifunctionalized m-terphenyls
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A facile one-step synthetic protocol toward multifunctionalized m-terphenyls 5 and sulfonyl m-terphenyls 6 is developed from substituted chalcones 1 and allyl sulfone 2 in good yields via a [3C+3C] annulation. The NaH-mediated annulation features transition metal catalyst-free condition. Chalcones 1 with the functional groups tolerance are easily prepared via Claisen-Schmidt condensation of substituted benzaldehydes 3 with acetophenone 4 in a qualitative yield under an aqueous alkaline methanolic solution.
- Chang, Meng-Yang,Chan, Chieh-Kai,Lin, Shin-Ying,Wu, Ming-Hao
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p. 9616 - 9624
(2013/10/22)
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- Synthesis of 1-substituted 3-aryl-5-aryl(hetaryl)-2-pyrazolines and study of their antitumor activity
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Three series of novel 1,3,5-trisubstituted 2-pyrazoline derivatives containing thiophene and benzodioxol moieties as potential antitumor agents were synthesized. The in vitro antitumor activity of the obtained compounds was determined at the National Canc
- Insuasty, Braulio,Chamizo, Leidy,Munoz, Jhon,Tigreros, Alexis,Quiroga, Jairo,Abonia, Rodrigo,Nogueras, Manuel,Cobo, Justo
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scheme or table
p. 275 - 286
(2012/06/30)
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- Stepwise palladium-catalyzed 1,4-addition of arylboronic acids to enones and regioselective Baeyer-Villiger oxidation for enantioselective synthesis of β-diaryl esters and (+)-(R)-tolterodine
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Baeyer-Villiger oxidation of chiral β-diaryl ketones synthesized by 1,4-addition of arylboronic acids to β-arylα,β-unsaturated ketones catalyzed by a palladium(2+)-chiraphos complex provided optically active β-diaryl esters up to 98% ee. The protocol was
- Kobayashi, Kenya,Nishikata, Takashi,Yamamoto, Yasunori,Miyaura, Norio
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experimental part
p. 1019 - 1025
(2009/04/13)
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- Development of a scalable process for CI-1020, a novel endothelin antagonist
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The process development of a route for preparing CI-1020 on pilot-plant scale is described in 55% overall yield. Hydrocyanation conditions are described which use acetone cyanohydrin catalyzed by tetramethylammonium hydroxide and which provide the desired
- Ellis, James E.,Davis, Edward M.,Dozeman, Gary J.,Lenoir, Edward A.,Belmont, Daniel T.,Brower, Phillip L.
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p. 226 - 233
(2013/09/07)
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