- Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors
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A series of 3-(3′,4′,5′-trimethoxyphenyl)-4-substituted 1H-pyrazole and their related 3-aryl-4-(3′,4′,5′-trimethoxyphenyl)-1-H-pyrazole regioisomeric derivatives, prepared as cis-rigidified combretastatin A-4 (CA-4) analogues, were synthesized and evaluated for their in vitro antiproliferative against six different cancer cell lines and, for selected highly active compounds, inhibitory effects on tubulin polymerization, cell cycle effects and in vivo potency. We retained the 3′,4′,5′-trimethoxyphenyl moiety as ring A throughout the present investigation, and a structure-activity relationship (SAR) information was obtained by adding electron-withdrawing (OCF3, CF3) or electron-releasing (alkyl and alkoxy) groups on the second aryl ring, corresponding to the B-ring of CA-4, either at the 3- or 4-position of the pyrazole nucleus. In addition, the B-ring was replaced with a benzo[b]thien-2-yl moiety. For many of the compounds, their activity was greater than, or comparable with, that of CA-4. Maximal activity was observed with the two regioisomeric derivatives characterized by the presence of a 4-ethoxyphenyl and a 3′,4′,5′-trimethoxyphenyl group at the C-3 and C-4 positions, and vice versa, of the 1H-pyrazole ring. The data showed that the 3′,4′,5′-trimethoxyphenyl moiety can be moved from the 3- to the 4-position of the 1H-pyrazole ring without significantly affecting antiproliferative activity. The most active derivatives bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. In vivo experiments, on an orthotopic murine mammary tumor, revealed that 4c inhibited tumor growth even at low concentrations (5 mg/kg) compared to CA-4P (30 mg/kg).
- Bortolozzi, Roberta,Brancale, Andrea,Camacho, Maria Encarnacion,Ferla, Salvatore,Grillo, Elisabetta,Hamel, Ernest,Mariotto, E.,Oliva, P.,Padroni, Chiara,Romagnoli, R.,Ronca, Roberto,Rruga, Fatlum,Salvador, Maria Kimatrai,Viola, Giampietro
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- Calcium carbide as the acetylide source: Transition-metal-free synthesis of substituted pyrazoles via [1,5]-sigmatropic rearrangements
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Under transition-metal-free conditions, calcium carbide was used as the acetylide source to react with a wide range of N-tosylhydrazones derived from aldehydes or ketones, affording various substituted pyrazoles in good yields with high regioselectivities. The transformations go through [3 + 2] cycloadditions followed by [1,5]-sigmatropic rearrangements, which are supported by deuterium-labeling experiments.
- Yu, Yue,Huang, Wei,Chen, Yang,Gao, Bingjie,Wu, Wanqing,Jiang, Huanfeng
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supporting information
p. 6445 - 6449
(2018/06/08)
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- Efficient and simple synthesis of 3-aryl-1H-pyrazoles
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Efficient preparation of 3-aryl-1H-pyrazoles by reaction of 1-protected-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoles with (het)aryl halides is described. The choice of THP protecting group is discussed.
- Gérard, Anne-Laure,Bouillon, Alexandre,Mahatsekake, Clément,Collot, Valérie,Rault, Sylvain
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p. 4665 - 4669
(2007/10/03)
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- The α-effect in reactions of sp-hybridized carbon atom: Michael-type reactions of 1-aryl-2-propyn-1-ones with primary amines
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Second-order rate constants (kN) have been measured for the Michael-type reaction of 1-(X-substituted phenyl)-2-propyn-1-ones (2a-f) with a series of primary amines in H2O at 25.0 ± 0.1 °C. A linear Bronsted-type plot with a small βnuc value (βnuc = 0.30) has been obtained for the reactions of 1-phenyl-2-propyn-1-one (2c) with non-α-nucleophile amines. Hydrazine is more reactive than other primary amines of similar basicity (e.g., glycylglycine and glycine ethyl ester) and results in a positive deviation from the linear Bronsted-type plot. The reactions of 2a-f with hydrazine exhibit a linear Hammett plot, while those with non-α-nucleophile amines give linear Yukawa-Tsuno plots, indicating that the electronic nature of the substituent X does not affect the reaction mechanism. The α-effect increases as the substituent X in the phenyl ring of 2a-f becomes a stronger electron-donating group. However, the magnitude of the α-effect for the reactions of 2a-f is small (e.g., kNhydrazine/kN glycylglycine = 4.6-13) regardless of the electronic nature of the substituent X. The small βnuc has been suggested to be responsible for the small α-effect. A solvent kinetic isotope effect (e.g., kNH2O/kND2O = 1.86) was observed for the reaction with hydrazine but absent for the reactions with non-α-nucleophile amines. The reactions with hydrazine and other primary amines have been suggested to proceed through a five-membered intramolecular H-bonding structure VI and a six-membered intermolecular H-bonding structure VII, respectively. The transition state modeled on VI can account for the substituent dependent α-effect and the difference in the solvent kinetic isotope effect exhibited by the reactions with hydrazine and other primary amines. It has been proposed that the βnuc value is more important than the hybridization type of the reaction site to determine the magnitude of the α-effect.
- Um, Ik-Hwan,Lee, Eun-Ju,Seok, Jin-Ah,Kim, Kyung-Hee
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p. 7530 - 7536
(2007/10/03)
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- 5-Hydroxy-2-pyrazolines and some of their 1-substituted analogs
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The use of 1,3-dicarbonyl compounds containing strong electron-withdrawing substituents (perfluoroalkyl, 4-nitrophenyl) at one of the carbonyl groups in reaction with hydrazine or its monosubstituted derivatives (4-nitro- and 2,4-dinitrophenylhydrazines) leads to the formation of stable intermediates for the synthesis of pyrazoles (5-hydroxy-2-pyrazolines) or their linear tautomers (hydrazones).
- Zelenin,Tugusheva,Yakimovich,Alekseev,Zerova
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p. 668 - 676
(2007/10/03)
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- Functionalised Pyrazoles through a Facile One-Pot Procedure from N-Tosyl-N-propargylhydrazine and Aryl Iodides or Vinyl Triflates
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Functionalised pyrazoles have been prepared in good overall yield through a facile one-pot procedure. The synthesis includes the palladium-catalysed coupling of the readily available N-tosyl-N-propargylhydrazine with aryl iodides or vinyl triflates, the palladium-catalysed annulation of the resulting N-tosyl-N-(1-aryl/vinyl-1-propyn3-yl)hydrazine and exposure of the reaction mixture arising from the annulation step to KOBut.
- Cacchi, Sandro,Fabrizi, Giancarlo,Carangio, Antonella
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p. 959 - 961
(2007/10/03)
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- POLARISED KETENE DITHIOACETALS. PART 50. REACTIONS OF α-AROYL-α-BROMOKETENE DITHIOACETALS WITH HYDRAZINE HYDRATE: FORMATION OF REARRANGED PYRAZOLES
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The reactions of α-aroyl-α-bromoketene dithioacetals (2a-c) with hydrazine hydrate yields unexpected pyrazoles, i.e. 3(5)-aryl-5(3)-4-bis(alkylthio)pyrazoles (9) in varying yields.The corresponding S-ethyl-α-bromoketene dithioacetals (2d) gave only the bis(ethylthio)pyrazole (7d) and 4-amino-4(3)-ethylthiopyrazole (9d) under similar conditions.The reactions of cyclic α-bromoketene dithioacetals (2e-g) with hydrazine hydrate on the other hand afforded only the dithiinopyrazole derivatives (7e-g) in high yields.The probable mechanisms for the formation of the pyrazoles (7)-(9) have been suggested.
- Singh, Gurdeep,IIa, Hiriyakkanavar,Junjappa, Hiriyakkanavar
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p. 1945 - 1950
(2007/10/02)
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