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The Nuclear Factor-kappa B (NF-κB) pathway is vital for immune system regulation and pro-inflammatory signaling. Many inflammatory disorders and diseases, including cancer, are linked to dysregulation of NF-κB signaling. When macrophages recognize the presence of a pathogen, the signaling pathway is activated, resulting in the nuclear translocation of the transcription factor, NF-κB, to turn on pro-inflammatory genes. Here, we demonstrate the effects of a novel microtubule depolymerizer, NT-07-16, a polysubstituted pyrrole compound, on this process. Treatment with NT-07-16 decreased the production of pro-inflammatory cytokines in RAW264.7 mouse macrophages. It appears that the reduction in pro-inflammatory mediators produced by the macrophages after exposure to NT-07-16 may be due to activities upstream of the translocation of NF-κB into the nucleus. NF-κB translocation occurs after its inhibitory protein, IκB-α is phosphorylated which signals for its degradation releasing NF-κB so it is free to move into the nucleus. Previous studies from other laboratories indicate that these processes are associated with the microtubule network. Our results show that exposure to the microtubule-depolymerizer, NT-07-16 reduces the phosphorylation of IκB-α and also decreases the association of NF-κB with tubulin which may affect the ability of NF-κB to translocate into the nucleus. Therefore, the anti-inflammatory activity of NT-07-16 may be explained, at least in part, by alterations in these steps in the NF-κB signaling pathway leading to less NF-κB entering the nucleus and reducing the production of pro-inflammatory mediators by the activated macrophages.

RAW 264.7 murine macrophages were exposed to the pyrrole-based compound 3,5-Dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester (JG-03-14), which is a known microtubule depolymerizing agent with antitumor activity [1,2,3]. In this study exposure to JG-03-14 reduced the production of pro-inflammatory molecules by macrophages activated with lipopolysaccharide (LPS). Treatment with the pyrrole-based compound decreased the concentration of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) released from the macrophages. Exposure to JG-03-14 also decreased TNF-α mRNA expression levels and the protein expression levels of inducible nitric oxide synthase (iNOS), the enzyme responsible for NO production in the activated macrophages. Furthermore, JG-03-14 treatment significantly changed the degradation profile of IκB-β, an inhibitor of the NF-κB transcription factor, which suggests that JG-03-14 may attenuate the activation of the LPS-induced NF-κB signaling pathway needed to produce the pro-inflammatory mediators. We conclude that JG-03-14 possesses anti-inflammatory properties.

The natural products lycogarubin (I), permethyl storniamide A (II), and lamellarin G trimethyl ether (III) are interesting biological active compounds.

Formylation of the pyrrole (I) provides a new pyrrole building block (III), which undergoes coupling reaction with various aryl trifluoroborates and aryl boronic acids.

Various indole derivatives (III), (VIII), and (IX) are coupled with hydrazines or α-amino esters to give indole appended pyrazoles and pyrroles.

A six-step sequence of reactions is applied to efficiently and stereoselectively prepare pyrrolones of type (VI).

A practical method for the high-yielding amine exchange of vinamidinium salts and their reduction to allylic amines (IV) is developed.

A variety of 2-substituted vinamidinium salts react with α-amino acid esters under basic conditions to produce 2-carbethoxy-4-substituted-pyrroles in good yield. The overall process represents a short and efficient synthesis of highly functionalized pyrroles from α-substituted acetic acid precursors. Such reactions may involve the intermediacy of azomethine ylids or «pentadienyl like» anions

The preparation of novel 2-(arylsulfonyl)vinamidinium salts is described. The reactions of these materials with amidines, hydrazine, hydroxylamine, sodium borohydride, and Grignard Reagents are presented along with an evaluation of their chemical behavior as compared to the 2-arylvinamidinium salts

The structure of a vinamidinium salt reduction product is revised and some reactions of related allylic ammonium salts with sulfur nucleophiles is presented.

The synthesis of two, vinylogous iminium salts, which contain an appended thiophene group, are described along with their conversion to thiophene substituted pyrimidines and pyrroles

Oxidative cleavage of a variety of electrophilic double bond substrates has been effected under mild reaction conditions by sodium metaperiodate or sodium hypochlorite catalyzed by ruthenium oxide.

β-Fluorovinamidinium salt (2), readily prepared fromN-(2, 3, 3-trifluoro-1-propenyl)trimethyl-ammonium iodide (1) and diethylamine, reacted with bifunctional hetero nucleophiles such as amidine and guanidine hydrochlorides in the presence of a base to afford regiospecifically monofluorinated pyrimidines4 in good yields. The one-pot procedure starting from1 was applicable for synthesizing heterocyclic compounds4 in almost comparable yields.

The reaction of unsymmetrical vinylogous iminum salts and related analogs with β-aminocrotononitrile to yield 2,3,6-trisubstituted pyridines with regioselective control is described.

The reaction of 1-substituted vinamidinium salts with sarcosine ethyl ester produced 2,3-disubstituted pyrroles; a similar reaction with glycine ethyl ester gave 2,5-disubstituted pyrroles. Reactions of related three-carbon synthons with sarcosine and glycine were studied under basic, neutral and acidic conditions which demonstrated the utility of these derivatives for the regiocontrolled preparation of disubstituted pyrroles.

The discovery of a catalytic effect of sand on the activity of KMnO4/NaIO4 or KMnO4/NaClO oxidant system provides a convenient method for double bond cleavage under mild conditions. An oxidative rearrangement of α-bromostyrene to 2-bromoacetophenone was also observed.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were synthesized in good yields by the reaction of N-(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl)trimethylammonium iodides (2), prepared from N-(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide (1), with secondary amines in MeCN at 70 °C for 1 h. The salts were also obtainable in comparable yields by the one-pot reaction of 1 with sodium polyfluoroalkoxide followed by treatment with amines.

β-Fluoro vinamidinium salt ( 1 ) reacted with 1.1 equiv. of methylene compounds activated with carbonyl or cyano groups in the presence of lithium diisopropylamide or sodium hydride and triethylamine in tetrahydrofuran at room temperature to give monofluorinated multifunctional dienaminones ( 3 ) and dienaminonitriles ( 5 ) in moderate to good yields. The reactions of 1 with 2.2 equiv. of enolates derived from β-keto esters at 80 °C gave the cyclization products, fluorinated isophthalates ( 6 ) in good yields, while a similar reaction with 2.2 equiv. of cyanoacetate and malononitrile produced the non-cyclic 1, 3-dienecarbonitriles ( 7 ) in excellent yields.

Novel β-polyfluoroalkoxy vinamidinium salts 3 and/or 4 were prepared in good yields by the reaction of N -(2-polyfluoroalkoxy-3,3-difluoro-1-propenyl) trimethylammonium iodides ( 2 ) with secondary amines in acetonitrile at 70 °C for 1 h. These vinamidinium salts readily reacted with bifunctional heteronucleophiles, such as amidines, guanidines and hydrazines, to give regiospecifically polyfluoroalkoxylated pyrimidines ( 6 ) and pyrazoles ( 8 ) in good yields. The one-pot procedure starting from N -(2,3,3-trifluoro-1-propenyl)trimethylammonium iodide ( 1 ), which was the precursor of 2 , was applicable for synthesizing the heterocyclic compounds in almost comparable yields with those obtained by the stepwise procedure using isolated 3 and 4 .

β-Fluorovinamidinium salt ( 1 ) reacted cleanly with a variety of Grignard reagents in tetrahydrofuran at room temperature, followed by acid workup, to produce the corresponding (Z)-α-fluoro-α,β-unsaturated aldehydes ( 3 ) in good to excellent yields.

β-Trifluoroethoxy vinamidinium salts 1 reacted smoothly with various types of the carbanions, generated by treatment of ketones, esters, amide and nitriles with LDA, to give the corresponding trifluoroethoxylated multifunctional dienamine derivatives 3 in moderate to good yields. On the other hand, the reaction of 1 with lithium acetylide and other carbanions derived from methyl compounds bearing sulfonyl, sulfinyl, and phosphonyl groups produced the corresponding α,β-unsaturated aldehydes 5 in good yields.

A series of benzonitriles has been reacted with sodium perborate in water and a cosolvent to produce the corresponding amides in good yield. The procedure is a mild and convenient alternative for the synthesis of aryl amides.

The enones (I) are epoxidized with aqueous sodium perborate to yield the acyloxiranes (II).

A series of terminal alkynes has been reacted with sodium perborate and mercuric acetate catalyst in acetic acid to produce 1-acetoxyalkan-2-ones in good yield. The reaction constitutes a mild and ...

The reaction of hydrazine hydrate with certain 2-substituted styryl-4-quinazolones results in the formation of a novel tricyclic heterocycle and not the previously reported acyl hydrazide. A mechanistic rationale is presented.

A variety of quaternary ammonium salts derived from 2-aryl-3-(N, N-dimethylamino)-1-propenes have been converted to the corresponding alkyl and fluoroalkyl ethers by displacement of the ammonium group. This procedure represents an efficient means for the construction of 2-aryl substituted allylic ethers.

A variety of organometallic reagents have been found to undergo regioselective reaction with 1-aryl-vinamidinium salts and 3-aryl-3-chloropropeniminium salts. The products of such reactions were found to be α,β-unsaturated ketones and chlorovinyl amines, respectively.