Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling’s clathrate hypothesis

Jackson, Patrice L.; Hanson, Clive D.; Farrell, Alanna K.; Butcher, Raymond J.; Stables, James P.; Eddington, Natalie D.; Scott, Kenneth R.

doi:10.1016/j.ejmech.2012.02.003

Cited by 27 publications

(9 citation statements)

References 35 publications

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“…The synthetic procedure involved amination of the respective β-diketones to generate the methylated enaminone intermediates, followed by acylation with the respective substituted acyl chloride to provide target compounds 4a – 9b , (Figure 3) [9,15,20]. We obtained all of the final compounds in moderate to good yields (14%–63%), as shown in Table 1.…”

Section: Resultsmentioning

confidence: 94%

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6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity

Amaye

Heinbockel

Woods

et al. 2018

IJERPH

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A small library of novel fluorinated N-benzamide enaminones were synthesized and evaluated in a battery of acute preclinical seizure models. Three compounds (GSA 62, TTA 35, and WWB 67) were found to have good anticonvulsant activity in the 6-Hz ‘psychomotor’ 44-mA rodent model. The focus of this study was to elucidate the active analogs’ mode of action on seizure-related molecular targets. Electrophysiology studies were employed to evaluate the compounds’ ability to inhibit neuronal activity in central olfactory neurons, mitral cells, and sensory-like ND7/23 cells, which express an assortment of voltage and ligand-gated ion channels. We did not find any significant effects of the three compounds on action potential generation in mitral cells. The treatment of ND7/23 cells with 50 µM of GSA 62, TTA 35, and WWB 67 generated a significant reduction in the amplitude of whole-cell sodium currents. Similar treatment of ND7/23 cells with these compounds had no effect on T-type calcium currents, indicating that fluorinated N-benzamide enaminone analogs may have a selective effect on voltage-gated sodium channels, but not calcium channels.

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Section: Resultsmentioning

confidence: 94%

“…In our previous studies, we found the enaminone system to be an excellent pharmacophore for anticonvulsant active analogs [6,7,8,9,10,11,12]. Enaminones, the enamine of β-dicarbonyl compounds, are well known as versatile building blocks for the synthesis of various heterocycles [12].…”

Section: Introductionmentioning

confidence: 99%

6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity

Amaye

Heinbockel

Woods

et al. 2018

IJERPH

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“…Zefirov and colleagues also synthesized several podophyllotoxin and epipodophyllotoxin derivatives bearing substituted isoxazole fragments during the time covered by this review [ 115 ]. They first synthesized the isoxazole unit from ethyl-2,4-dioxopentanoate ( 79 ) following a known procedure [ 116 , 117 , 118 ], as shown in Scheme 16 . Then, bromination, iodination, and nitration at position 4 of the isoxazole ring was carried out following several procedures previously described [ 119 , 120 , 121 ].…”

Section: C-ring Modifications Of the Podophyllotoxin Skeletonmentioning

confidence: 99%

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Miranda-Vera,

Hernández,

García-García

et al. 2023

Pharmaceutics

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Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

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“…They are also used as precursors for the synthesis of various types of compounds like N-substituted carbazolones [7], peptides [8], quinolines [9,10], azocompounds [11,12], α,β-aminoacids [13,14] that serve important roles in asymmetric catalysis via chelating agents [15]. Enaminones are known to affect several physiological functions themselves or are precursors for such molecules, in particular as anticonvulsant [16], anti-epileptic [17], anti-inflammatory [18] and antitumor agents [19,20,21].…”

Section: Introductionmentioning

confidence: 99%

Efficient PPA-SiO2-catalyzed Synthesis of β-enaminones Under Solvent-Free Conditions

et al. 2013

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An efficient method has been developed for the synthesis of β-enaminones under solvent-free reaction conditions using PPA-SiO 2 as catalyst. The reaction yields were good to excellent (up to 90%). This methodology affords high selectivity and good tolerance of a variety of different functional groups present on both aromatic and aliphatic amines. In addition, the methodology is environmentally benign and cost-effective due to absence of solvent and easy work-up.

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Enaminones 12. An explanation of anticonvulsant activity and toxicity per Linus Pauling’s clathrate hypothesis

Cited by 27 publications

References 35 publications

6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity

6 Hz Active Anticonvulsant Fluorinated N-Benzamide Enaminones and Their Inhibitory Neuronal Activity

Podophyllotoxin: Recent Advances in the Development of Hybridization Strategies to Enhance Its Antitumoral Profile

Efficient PPA-SiO2-catalyzed Synthesis of β-enaminones Under Solvent-Free Conditions

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