Styrylpyrazoles, styrylisoxazoles, and styrylisothiazoles. Novel 5-lipoxygenase and cyclooxygenase inhibitors

Flynn, Daniel L.; Belliotti, Thomas R.; Boctor, Amal M.; Connor, David T.; Kostlan, Catherine R.; Nies, Donald E.; Ortwine, Daniel F.; Schrier, Denis J.; Sircar, J. C.

doi:10.1021/jm00106a006

Cited by 92 publications

(57 citation statements)

References 3 publications

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“…The wide range of biological activities of pyrazoles has made them popular synthetic targets [118][119][120]. The most popular method for the preparation of pyrazoles unsubstituted at the nitrogen atoms involves condensation of hydrazine with β-dicarbonyl compounds.…”

Section: Pyrazolementioning

confidence: 99%

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

Beagle

2015

Topics in Heterocyclic Chemistry

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Application of benzotriazole methodology for the preparation of nitrogen-containing heterocyclic compounds is summarized in this review. The characteristic advantages of benzotriazole are first briefly considered followed by an overview of its use in the synthesis of heterocycles organized by the ring size. Finally, the use of benzotriazole in the synthesis of bicyclic systems is showcased in only selected examples.

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Section: Pyrazolementioning

confidence: 99%

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

Beagle

2015

Topics in Heterocyclic Chemistry

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“…Although another characteristic of these agents is their potent inhibition of trypsin, elastase, and neutral cathepsin activities, in our hands they were less potent inhibitors of collagenase type I and II activities with IC50 values from 10-to 10-5M (data not shown ). The agents proved to be dual inhibitors of prostaglandin cyclo-oxygenase and 5'-lipoxygenase (27,28), with IC50 values in the range of 10-6M. IC-21 macrophages incubated with the agents secreted less interleukin-1 (Il-1) and tumor necrosis factor-a (TNFa) cytokines (Figures 32,33).…”

Section: Introductionmentioning

confidence: 99%

Hypolipidemic, Anti-Obesity, Anti-Inflammatory, Anti-Osteoporotic, and Anti-Neoplastic Properties of Amine Carboxyboranes

Hall¹,

Chen²,

Rajendran³

et al. 1994

Environmental Health Perspectives

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The amine-carboxyborane derivatives were shown to be effective antineoplastic/cytotoxic agents with selective activity against single-cell and solid tumors derived from murine and human leukemias, lymphomas, sarcomas, and carcinomas. The agents inhibited DNA and RNA synthesis in preference to protein synthesis in L1210 lymphoid leukemia cells. Inosine-monophospate dehydrogenase apparently is a target site of the compounds; similar effects on phosphoribosyl-pyrophosphate amido transferase, orotidine-monophosphate decarboxylase, and both nucleoside and nucleotide kinases were observed. Deoxyribonucleotide pool levels were reduced in the cells; DNA strand scission was observed with the agents. In rodents, the amine carboxyboranes were potent hypolipidemic agents, lowering both serum cholesterol and triglyceride concentrations, in addition to lowering cholesterol content of very low-density lipoprotein and low-density lipoprotein (LDL) and elevating high-density lipoprotein (HDL) cholesterol concentrations. De novo regulatory enzymes involved in lipid synthesis were also inhibited (e.g., hypocholesterolemic 3-hydroxy-3-methyl-Coenzyme A reductase, acyl-Coenzyme A cholesterol acyltransferase, and sn-glycerol-3-phosphate acyltransferase). Concurrently, the agents modulated LDL and HDL receptor binding, internalization, and degradation, so that less cholesterol was delivered to the plaques and more broken down from esters and conducted to the liver for biliary excretion. Tissue lipids in the aorta wall of the rat were reduced and fewer atherosclerotic morphologic lesions were present in quail aortas after treatment with the agents. Cholesterol resorption from the rat intestine was reduced in the presence of drug. Genetic hyperlipidemic mice demonstrated the same types of reduction after treatment with the agents. The agents would effectively lower lipids in tissue based on the inhibition of regulatory enzymes in pigs. These findings should help improve domestic meat supplies from fowl and pigs. The amine-carboxyboranes were effective anti-inflammatory agents against septic shock, induced edema, pleurisy, and chronic arthritis at 2.5 to 8 mg/kg. Lysosomal and proteolytic enzyme activities were also inhibited. More significantly, the agents were dual inhibitors of prostaglandin cyclooxygenase and 5-lipoxygenase activities. These compounds also affected cytokine release and white cell migration. Subsequent studies showed that the aminecarboxyboranes were potent anti-osteoporotic agents reducing calcium resorption as well as increasing calcium and proline incorporation into mouse pup calvaria and rat UMR-106 collagen. -Environ Health Perspect 102(Suppl 3): 21-30 (1994)

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“…Besides the use of 1 as a seasoning and traditional coloring agent, its pharmacological action as antioxidant, antitumoral and anticancer activities 1,2 is widely referred to in the literature.Flynn et al 2 have prepared some heterocycle derivatives of 1, including a pyrazole derivative and the pyrazole corresponding to tetrahydrocurcumin. The former compound was obtained in very low yield, in contrast to the latter, although its antioxidant activity was better than exerted by curcumin.…”

mentioning

confidence: 99%

“…Flynn et al 2 have prepared some heterocycle derivatives of 1, including a pyrazole derivative and the pyrazole corresponding to tetrahydrocurcumin. The former compound was obtained in very low yield, in contrast to the latter, although its antioxidant activity was better than exerted by curcumin.…”

mentioning

confidence: 99%

Crystal Structure of {Acetic acid 4-[7-(4-acetoxy-3-methoxyphenyl)-3,5-dioxoheptyl]-2-methoxy ester-03.05}-boron difluoride: A Boron Complex of Acetylated Tetrahydrocurcumin Derivative

Lozada¹,

Lobato²,

Enríquez³

et al. 2004

Anal. Sci. X

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Curcumin 1 belongs to a family of naturally occurring diarylheptanoids isolated from several curcuma species (Curcuma longa, Curcuma zedoaria, etc.). Besides the use of 1 as a seasoning and traditional coloring agent, its pharmacological action as antioxidant, antitumoral and anticancer activities 1,2 is widely referred to in the literature.Flynn et al. 2 have prepared some heterocycle derivatives of 1, including a pyrazole derivative and the pyrazole corresponding to tetrahydrocurcumin. The former compound was obtained in very low yield, in contrast to the latter, although its antioxidant activity was better than exerted by curcumin.As a part of our studies about new curcumin derivatives and other functional β-diketones analogs, 3 we prepared 2 by the acetylation of 1 with acetic anhydride and pyridine. Then, 2 was reduced by catalytic hydrogenation with Pd/C (5%) in AcOEt to obtain 3. Compound 4 ({acetic acid 4-[7-(4-acetoxy-3-methoxyphenyl)-3,5-dioxoheptyl]-2-methoxy ester-0 3.0 5 }-boron difluoride) was obtained from the reaction of 3 with BF3(Et2O), as depicted in Scheme 1. This compound is very stable, and once that it is formed no reaction was observed with the different nucleophiles used. In this report we describe the crystal structure of 4. The unusual stability of the boroncomplex 4 provides useful data for understanding the limitations of BF3(Et2O) when used as a Lewis acid catalyst in nucleophilic reactions of 3.X-ray data for crystals of the title compound were collected by graphite-monochromatized Mo Kα radiation at 293 K. No absorption correction was applied. The structure was solved by direct methods and refined by full-matrix least-squares with anisotropic temperature factors for the non-hydrogen atoms. O6 and O7 show disorder with occupancy factors for O6;O6A and O7;O7A of 0.694(9); 0.306(9)Å for both sets of atoms. The positions of all H atoms were calculated geometrically and a riding model was used in their refinement, with C-H distances in the range of 0.93 -0.97 Å and Uiso(H) = 1.2 Ueq (C). The software used to prepare the material for publication was PARST97.4 Table 1

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Styrylpyrazoles, styrylisoxazoles, and styrylisothiazoles. Novel 5-lipoxygenase and cyclooxygenase inhibitors

Cited by 92 publications

References 3 publications

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

Benzotriazole-Mediated Synthesis of Nitrogen-Containing Heterocycles

Hypolipidemic, Anti-Obesity, Anti-Inflammatory, Anti-Osteoporotic, and Anti-Neoplastic Properties of Amine Carboxyboranes

Crystal Structure of {Acetic acid 4-[7-(4-acetoxy-3-methoxyphenyl)-3,5-dioxoheptyl]-2-methoxy ester-03.05}-boron difluoride: A Boron Complex of Acetylated Tetrahydrocurcumin Derivative

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