Aroylacrylic Acids Research Articles

Synthesis and Anticancer Activity of Novel Nonfused Bicyclic Thiazolidinone Derivatives

A series of new 2-{4-oxo-2-[(4-oxothiazolidin-2-ylidene)-hydrazono]-thiazolidin-5-yl}-N-arylacetamides ( 4a–e ), 5-(2-oxo-2-aryl-ethyl)-2-[(4-oxothiazolidin-2-ylidene)-hydrazono]-thiazolidine-4-ones ( 5a–d ), 2-(4-oxo-2-[(2-oxothiazolidin-4-ylidene)-hydrazono]-thiazolidin-5-yl)-N-arylacetamides ( 7a–e ), and 5-(2-oxo-2-aryl-ethyl)-2-[(2-oxothiazolidin-4-ylidene)-hydrazono]-thiazolidine-4-ones ( 8a–d ) have been synthesized starting from 2-thioxothiazolidin-4-one and 4-thioxothiazolidin-2-one through a multistep reaction sequence. 2-Thioxothiazolidin-4-one was alkylated via the intermediate formation of the triethylammonium salt 1 by ethyl chloroacetate. Compound 2 and 4-thioxothiazolidin-2-one reacted with thiosemicarbazides to give the 1-(4-thiazolidinone-2-ylidene)-4-R-thiosemicarbazones ( 3a,b ) and 1-(2-thiazolidinone-4-ylidene)thiosemicarbazones ( 6a,b ), respectively. Following [2+3]-cyclization of thiazolidinone-substituted thiosemicarbazones ( 3a,b and 6a,b) with N-arylmaleimides and aroylacrylic acids as equivalents of dielectrophilic synthon [C2]2 +, novel non-fused bicyclic thiazolidinones ( 4a–e, 5a–d, 7a–e, 8a–d ) were synthesized. The structures of the new compounds ( 4a–e, 5a–d, 7a–e, 8a–d ) were established on the basis of their elemental analysis and 1H NMR and mass spectral data. Eight of the synthesized compounds were tested, and three of them displayed different levels of antitumor activity. The most efficient antitumor agent—2-{4-oxo-3-furylmethyl-2-[(4-oxothiazolidin-2-ylidene)-hydrazono]-thiazolidin-5-yl}-N-4-chlorophenylacetamide ( 4d ) was found to be active against leukemia, melanoma, lung, colon, CNS, ovarian, renal, prostate, and breast cancer cell lines with mean lgGI50 and lgTGI values of –5.35 and –4.78, respectively.

397 POSTER Potentiation of the antitumor activity of bortezomib, a proteasome inhibitor, by the combination with EGFR inhibitors in human cancer cell lines

A series of novel pyridazinone derivatives bearing benzenesulfonamide moiety (2a–h) has been synthesized by the condensation of appropriate aroylacrylic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Five derivatives (2a, 2b, 2d, 2g and 2h) were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute. The 2h showed remarkable activity against SR (leukemia) and NCI-H522 (non-small cell lung) with a GI50 value of less than 0.1 μM. It also displayed good activity against leukemia (CCRF-CEM, HL-60 (TB), K-562, MOLT-4, RPMI-8226), non-small cell lung cancer (NCI-H460), colon (HCT-116, HCT-15, HT29, KMI2, SW-620), CNS (SF-295), melanoma (MALME-3M, M14, MDA-MB-435 SK-MEL-5), ovarian (OVCAR-3, NCI/ADR-RES) and breast (MCF7) cancer cell lines with a GI50 less than 1.0 μM. The acute toxicity study of 2h indicated that it is well tolerated intra-peritoneally (400 mg/kg) by athymic nude mice. The 2h may possibly be used as lead compound for developing new anticancer agents.

Crystallization-induced asymmetric transformation. Application to conjugate addition of benzylamine to amides of benzoylacrylic acid

Graphic Adducts of the conjugate addition of benzylamine to enantiopure amides of aroylacrylic acid possess high enantiomeric and diastereomeric purity. A high degree of stereoselectivity has been achieved by means of crystallization-induced asymmetric transformation. A practical synthesis leading to dipeptides containing homophenylalanine is depicted.

Crystallization-induced asymmetric transformation. Application to conjugate addition of benzylamine to amides of benzoylacrylic acid

Adducts of the conjugate addition of benzylamine to enantiopure amides of aroylacrylic acid possess high enantiomeric and diastereomeric purity. A high degree of stereoselectivity has been achieved by means of crystallization-induced asymmetric transformation. A practical synthesis leading to dipeptides containing homophenylalanine is depicted.

Regioselective Interaction of β‐Aroylacrylic Acids with 1,2‐Diaminoimidazoles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Regioselective interaction of β-aroylacrylic acids with 1,2-diaminoimidazoles

α-Hetarylation products, which subsequently underwent cyclization into imidazopyridazines, were detected in the reactions of aroylacrylic acids with 1,2-diamino-4-phenylimidazole.

ChemInform Abstract: Crystallization‐Induced Dynamic Resolution (CIDR) and Its Application to the Synthesis of Unnatural N‐Substituted Amino Acids Derived from Aroylacrylic Acids.

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Crystallization-induced dynamic resolution (CIDR) and its application to the synthesis of unnatural N-substituted amino acids derived from aroylacrylic acids

A highly stereoselective conjugate addition of chiral amino alcohols affords a simple and inexpensive access to a wide variety of N-functionalized homophenylalanine derivatives. Limitations and conditions for application of CIDR to this system were studied.

Regioselective Base-induced Condensations of Acrylic Acid Derivatives

The orientation of cyclization of the reaction of methyl aroylacrylate (1) and aroylacrylic acid (8) with ethyl acetoacetate and/or thiourea leading to the formation of 4-aroylmethylcyclopentane-1,3-dione (2) 5-aryl-3-oxocyclohexene-1,2-dicarboxylic acid (9), 2-imino-5-aroylmethylthiazolidin-4-one (11) and 6-aryl-2-sulfonylpyrimidine-4-carboxylic acid (14) depends on the medium employed; some compounds show moderate antiviral activities against tobacco necrosis virus.

Regioselective Base-induced Condensations of Acrylic Acid Derivatives

The orientation of cyclization of the reaction of methyl aroylacrylate (1) and aroylacrylic acid (8) with ethyl acetoacetate and/or thiourea leading to the formation of 4-aroylmethylcyclopentane-1,3-dione (2) 5-aryl-3-oxocyclohexene-1,2-dicarboxylic acid (9), 2-imino-5-aroylmethylthiazolidin-4-one (11) and 6-aryl-2-sulfonylpyrimidine-4-carboxylic acid (14) depends on the medium employed; some compounds show moderate antiviral activities against tobacco necrosis virus.

Decarboxylation-based traceless linking with aroyl acrylic acids

β-Keto carboxylic acids are known to decarboxylate readily. In our pursuit to synthesize β-indolinyl propiophenones, we have exploited this chemistry as a mean of establishing a traceless handle. 2-Aroyl acrylic acids have been esterified to a trityl resin, after which Michael-type addition of indolines have been performed. Upon cleavage, the products are decarboxylated, and the β-indolinyl propiophenones are isolated. The reaction conditions have been optimized, and a small library has been prepared.

High-performance liquid chromatographic determination of aliphatic thiols with aroylacrylic acids as fluorogenic percolumn derivatization reagents

The use of the methyl ester of 4-(6-methoxynaphthalen-2-yl)-4-oxo-2-butenoic acid as a fluorogenic labelling regent for the high-performance liquid chromatography (HPLC) of biologically important thiols (glutathione, cysteine, acetylcysteine, homocysteine, cysteamine, sodium 2-mercaptoethanesulphonate and thiola) was investigated. The compound reacts selectively and rapidly (10 min at ambient temperature and pH 7.5) with the thiols to give fluorescent adducts that can be separated by reversed-phase HPLC and detected fluororimetrically (λ em = 450 nm; λ em = 310 nm). Applications to the determination of l-cysteine and mesna in pharmaceutical formulations are described.

Analysis of thiols by HPLC after fluorescent prelabelling with 4-(6-methylnaphthalen-2-yl)-4-oxobuten-2-oic acid

The use of 4-(6-methylnaphthalen-2-yl)-4-oxobuten-2-oic acid as a fluorogenic reagent in pre-column derivatization for the high-performance liquid chromatography (HPLC) of biologically important thiols (L-cysteine, glutathione, N-acetylcysteine, homocysteine and mercaptopropionylglycine) was investigated. The aroylacrylic acid reacts selectively and rapidly (15 min. at room temperature) with the thiol compounds to give stable fluorescent adducts which can be separated by reversedphase HPLC and detected fluorometrically (λex 300nm); λem 445nm). The experimental conditions for the thiol derivatization and chromatographic separation are discussed. Applications to the determination of N-acetylcysteine, mercaptopropionylglycine and cysteine are described.

ChemInform Abstract: Alkylation Reaction and Michael Condensation of 3‐Aroylacrylic Acids.

AbstractThe aroylacrylic acid (Ia) is coupled with p‐xylene (II) and then cyclized with the hydrazines (IV) or in the presence of acetic anhydride, yielding the diarylpyridazinones (V) or the dihydrofuranone (VI).

Use of 4-(6-methylnaphthalen-2-yl)-4-oxobut-2-enoic acid as a reagent for the spectrophotometric and fluorimetric determination of aliphatic thiol drugs.

The aroylacrylic acid 4-(6-methylnaphthalen-2-yl)-4-oxobut-2-enoic acid is proposed as a useful reagent for the spectrophotometric and fluorimetric determination of aliphatic thiol compounds. Under mild reaction conditions (pH 7.4, room temperature) the compound reacts rapidly (reaction complete in 15 min) and selectively with thiol compounds to give stable fluorescent thiol adducts. The adducts can be determined in the presence of the reagent excess by spectrophotometric (conventional and second- or third-derivative procedures) and fluorimetric (λem.= 445 nm, λex.= 300 nm) methods. All the described procedures have been successfully applied to the determination of thiol drugs such as N-acetylcysteine, mercaptopropionylglycine and captopril in commerical dosage forms.

Reaction of ?-aroylacrylic acids with 1-substituted 3,4-dihydroisoquinolines

The reactions of β-aroylacrylic acids and their methyl esters with 1-methyl- and 1-benzyl-3,4-dihydroisoquinolines lead to the formation of α-substituted β-aroylpropionic acids and their esters, which undergo cyclization to benzopyrrocolinone derivatives.

Nucleophilic addition of indole and its derivatives to ?-aroylacrylic acids

Condensation of Β-benzoyl- and Β-toluylacrylic acids with indole and its derivative gave Β-benzoyl- and Β-toluyl-α-(3-indolyl)propionic acids and their derivatives.

Synthesis of ? aroylac rylic acids and their amides

1. Conditions for the hydrolysis of aryl β -cyanovinyl ketones to the corresponding β -aroylacrylic acids and their amides have been established. 2. The method of hydrolysis affords the normally difficult to obtain ortho-substituted β -aroylacrylic acids, in particular β-(o-nitrobenzoyl)acrylic acid, which can be converted to D,L-kynurenine.

A Novel Synthesis for Aroylacrylic Acids

THIS preliminary investigation was undertaken in an effort to apply the Doebner condensation to the synthesis of aroylacrylic acids according to the following equation: