Modified knoevenagel condensations. Synthesis of (E)-3-alkenoic acids.

Ragoussis, Nikitas

doi:10.1016/s0040-4039(00)95658-2

Cited by 69 publications

(26 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Introduction of an sp 2 hybridized group on the PYT ring at the R 3 position was accomplished by a Knoevenagel condensation between PYT analogs with aldehydes catalyzed by a mixture of benzoic acid and piperidine. 18 …”

Section: Chemistrymentioning

confidence: 99%

Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

Xia

Benmohamed²,

Kim

et al. 2011

J. Med. Chem.

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness, paralysis, and death, most often from respiratory failure. The only FDA approved drug for the treatment of ALS, riluzole, only extends the median survival in patients by 2–3 months. There is an urgent need for novel therapeutic strategies for this devastating disease. Using a high-throughput screening assay targeting an ALS cultured cell model (PC12-G93A-YFP cell line), we previously identified three chemotypes that were neuroprotective. We present a further detailed analysis of one promising scaffold from that group, pyrimidine-2,4,6-triones (PYTs), characterizing a number of PYT analogs using SAR and ADME. The PYT compounds show good potency, superior ADME data, low toxicity, brain penetration, and excellent oral bioavailability. Compounds from this series show 100% efficacy in the protection assay with a good correlation in activity between the protection and protein aggregation assays. The modifications of the PYT scaffold presented here suggest that this chemical structure may be a novel drug candidate scaffold for use in clinical trials in ALS.

show abstract

Section: Chemistrymentioning

confidence: 99%

Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

Xia

Benmohamed²,

Kim

et al. 2011

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…This same product was obtained when the reaction was carried out at 0 o C, together with 3,3-dimethyloxindole 418 (Scheme 99). Isatins fail to yield Knoevenagel condensation products with malonic acid 419 . However, malonic acid can be condensed with isatin in a mixture of ethanol and pyridine, in which the initial condensation product suffers decarboxylation, furnishing an acetic acid derivative.…”

Section: Scheme 96mentioning

confidence: 99%

The chemistry of isatins: a review from 1975 to 1999

Silva¹,

Garden²,

Pinto³

2001

J. Braz. Chem. Soc.

834

447

View full text Add to dashboard Cite

Isatinas (1H-indol-2,3-diona) são compostos de grande versatilidade sintética, podendo ser utilizados na obtenção de diversos sistemas heterociclos, como derivados indólicos e quinolínicos, o que as tornam importantes matérias-primas na síntese de fármacos. Isatinas também têm sido detectadas em tecidos de mamíferos, o que tem despertado o interesse em seu estudo como moduladores em diversos processos bioquímicos. Os avanços na aplicação de isatinas em síntese orgânica, bem como na compreensão de seus efeitos biológicos e farmacológicos nos últimos vinte e cinco anos encontram-se relatados nesta revisão e seus respectivos materiais suplementares.Isatins (1H-indole-2,3-dione) are synthetically versatile substrates, where they can be used for the synthesis of a large variety of heterocyclic compounds, such as indoles and quinolines, and as raw material for drug synthesis. Isatins have also been found in mammalian tissue and their function as a modulator of biochemical processes has been the subject of several discussions. The advances in the use of isatins for organic synthesis during the last twenty-five years, as well as a survey of its biological and pharmacological properties are reported in this review and in the accompanying supplementary information.

show abstract

“…Hept-3-enoic acid (85%) was purchased from TCI Chemicals (Portland, OR, USA) and was used as received. Although not explicitly labeled as such, 1 H NMR indicated greater than 85% trans-isomer when compared with an authentic sample [28]. 6-Methoxy-2-naphthaldehyde (1) was purchased from Avocado Research Chemicals (Heysham, UK).…”

Section: Reagentsmentioning

confidence: 99%

Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies

Jones

Wolf

Morisseau

et al. 2005

Analytical Biochemistry

147

233

View full text Add to dashboard Cite

Inhibition of the mammalian soluble epoxide hydrolase (sEH) is a promising new therapy in the treatment of disorders resulting from hypertension and vascular inflammation. A spectrophotometric assay (4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate, NEPC) is currently used to screen libraries of chemicals; however this assay lacks the required sensitivity to differentiate the most potent inhibitors. A series of fluorescent α-cyanoester and α-cyanocarbonate epoxides that produce a strong fluorescent signal on epoxide hydrolysis by both human and murine sEH were designed as potential substrates for an in vitro inhibition assay. The murine enzyme showed a broad range of specificities, whereas the human enzyme showed the highest specificity for cyano(6-methoxynaphthalen-2-yl)methyl trans- [(3-phenyloxiran-2-yl) methyl] carbonate. An in vitro inhibition assay was developed using this substrate and recombinant enzyme. The utility of the fluorescent assay was confirmed by determining the IC 50 values for a series of known inhibitors. The new IC 50 values were compared with those determined by spectrophotometric NEPC and radioactive tDPPO assays. The fluorescent assay ranked these inhibitors on the basis of IC 50 values, whereas the NEPC assay did not. The ranking of inhibitor potency generally agreed with that determined using the tDPPO assay. These results show that the fluorescence-based assay is a valuable tool in the development of sEH inhibitors by revealing structure-activity relationships that previously were seen only by using the costly and labor-intensive radioactive tDPPO assay. KeywordsSoluble epoxide hydrolase; α-Cyanoester; α-Cyanocarbonate; Kinetic assay; Fluorescent substrateThe soluble epoxide hydrolase (sEH, EC 3.3.2.3) 1 is a member of the α/β-hydrolase fold family of enzymes [1] and catalyzes the hydrolysis of an epoxide to its corresponding diol through the catalytic addition of a water molecule [2]. The endogenous substrates for the sEH include epoxides of arachidonic acid [3,4] and linoleic acid [5,6]. Arachidonic acid epoxides (epoxyeicosatrienoic acid epoxides, EETs) are known modulators of blood pressure [7,8] and vascular permeability [9,10]. It has been shown that sEH inhibition not only lowers blood * Corresponding author. Fax: +1 530 752 1537. E-mail address:bdhammock@ucdavis.edu (B.D. Hammock).. 1 Abbreviations used: sEH, soluble epoxide hydrolase; EET, epoxyeicosatrienoic acid epoxides; NEPC, 4-nitrophenyl-trans-2,3-epoxy-3-phenylpropyl carbonate; TEA, triethylamine; TLC, thin-layer chromatography; TMS, tetramethylsilane; ppm, parts per million; oa-TOF, orthogonal acceleration time-of-flight; THF, tetrahydrofuran; m-CPBA, m-chloroperbenzoic acid; BSA, bovine serum albumin; RFU, relative fluorescent units; OD, optical density; DMSO, dimethyl sulfoxide; EDCI, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; tDPPO, [ 3 H] pressure in rodent models but also offers protection against hypertension-related renal damage [4,11,12].For the past 6 years, we have investi...

show abstract

Modified knoevenagel condensations. Synthesis of (E)-3-alkenoic acids.

Cited by 69 publications

References 13 publications

Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

Pyrimidine-2,4,6-trione Derivatives and Their Inhibition of Mutant SOD1-Dependent Protein Aggregation. Toward a Treatment for Amyotrophic Lateral Sclerosis

The chemistry of isatins: a review from 1975 to 1999

Fluorescent substrates for soluble epoxide hydrolase and application to inhibition studies

Contact Info

Product

Resources

About