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Regioselective Preparation of Benzo[b]furans from Phenols and alpha-Bromoketones.

Regioselective Preparation of Benzo[b]furans from Phenols and alpha-Bromoketones. Journal of Organic Chemistry. 2012, vol 77, pp 266-275.

http://pubs.acs.org/doi/abs/10.1021/jo201841y

Abstract: In this paper, a fully regiocontrolled synthesis of either 2- and 3-substituted benzo[b]furans is described. Direct reaction between phenols and α-bromoacetophenones in the presence of neutral alumina yields 2-substituted benzo[b]furans with complete regiocontrol. When a basic salt such as potassium carbonate is used, the corresponding 2-oxoether is obtained. Cyclization of these latter compounds promoted by neutral alumina yields the corresponding 3-substituted benzo[b]furans. Using the former method, Moracin M and other analogues can be obtained from commercial sources in two preparative steps. DFT calculations provide reasonable reaction paths to understand the formation of 2-substituted benzo[b]furans.

Regiochemistry of the microwave-assisted reaction between aromatic amines and a-bromoketones to yield substituted 1H-indoles.

Regiochemistry of the microwave-assisted reaction between aromatic amines and a-bromoketones to yield substituted 1H-indoles. Organic and Biomolecular Chemistry. 2008, vol 6(10), pp. 1763-1772

http://pubs.rsc.org/en/content/articlelanding/2008/ob/b719641e#!divAbstract

Abstract: The scope and regioselectivity of the Bischler (or Bischler-Möhlau) reaction between aromatic amines and α-bromoketones has been studied by computational and experimental techniques. It has been found that in many cases the reaction yields are improved under microwave irradiation and working in the absence of solvent. When di- and trisubstituted amines are used as substrates the regioselectivity of the reaction is different to that obtained with the corresponding primary anilines. The reaction between benzene-1,2-diamine and α-bromoacetophenones under the same conditions yields 2-substituted quinoxalines instead of indoles. Finally, when pyridin-2-amines and pyrimidine-2-amines are allowed to react with the corresponding α-bromoacetophenones, the corresponding imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines are obtained, respectively.

Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity.

Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity. Oncogene 2009, vol 28(11), pp. 1477-1484.

http://www.nature.com/onc/journal/v28/n11/abs/onc2008501a.html

Abstract: Histone deacetylases (HDACs) play a key role in the regulation of gene expression and chromatin structure, and drugs targeting these enzymes might have an important impact in the treatment of human cancer. Herein, we report the characterization of (1H)-pyrroles as a new subfamily of HDAC inhibitors obtained by computational modeling of class-I human HDACs. From a functional standpoint, (1H)-pyrroles are powerful inductors of acetylation of histones H3 and H4, and restore the expression of growth-inhibitory genes. From a cellular view, these compounds cause a marked decrease in the viability of cancer cells in vitro and in vivo, associated with a cell-cycle arrest at G2/M and an inhibition of angiogenesis. Thus, (1H)-pyrroles emerge as a novel group of HDAC inhibitors with promising antitumoral features.

Pharmacokinetics and tissue distribution of Kendine 91, a novel histone deacetylase inhibitor, in mice.

Pharmacokinetics and tissue distribution of Kendine 91, a novel histone deacetylase inhibitor, in mice. Cancer Chemotherapy and Pharmacology, 2009, vol 64(1), pp 153-159.

http://link.springer.com/article/10.1007%2Fs00280-008-0857-9

Abstract: Purpose : The present investigation was undertaken to characterize the pharmacokinetics and oral bioavailability of Kendine 91 in mice and to compare it with other HDAC (histone deacetylases) inhibitors. Methods: After administration of a single intravenous dose (10 mg/kg) or a single oral dose (50 mg/kg) blood and tissues samples were collected and analysed by HPLC/MS/MS. Results: Elimination half-life was higher than that of SAHA (5.87 vs. 0.38 h after intravenous (IV) administration and 10.29 versus 0.75 h after oral administration). Absolute oral bioavailability was found to be 18%. Total body clearance (7.72 l/h/kg) was greater than the hepatic blood flow of 5.4 l/h/kg in mice and larger than glomerular filtration rate in mice (0.84 l/h/kg). Tissue levels and distribution volume indicate a high capacity of Kendine 91 to distribute into tissues. Conclusions: This preliminary pharmacokinetic evaluation prompts us to believe that it is worth pursuing further development of Kendine 91 as an anticancer drug.

Formation of γ-Oxoacids and 1H-Pyrrol-2(5H)-ones from α,β-Unsaturated Ketones and Ethyl Nitroacetate.

Formation of γ-Oxoacids and 1H-Pyrrol-2(5H)-ones from α,β-Unsaturated Ketones and Ethyl Nitroacetate. Journal of Organic Chemistry 2010, vol 75, pp 7435-7438.

http://pubs.acs.org/doi/abs/10.1021/jo101388x

Abstract: Michael addition of ethyl nitroacetate on α,β-unsaturated ketones followed by Nef oxidation under hydrolytic conditions yields γ-oxoacids instead of the corresponding α,δ-dioxoesters. A concerted decarboxylation step is proposed on the basis of computational results. Finally, conversion of the γ-ketoacids thus prepared into 1H-pyrrol-2(5H)-ones by reaction with primary amines under Paal−Knorr conditions is also reported.

 

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